CN105061410A - Afatinib, preparation method therefor and application thereof - Google Patents
Afatinib, preparation method therefor and application thereof Download PDFInfo
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- CN105061410A CN105061410A CN201510483400.7A CN201510483400A CN105061410A CN 105061410 A CN105061410 A CN 105061410A CN 201510483400 A CN201510483400 A CN 201510483400A CN 105061410 A CN105061410 A CN 105061410A
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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
Abstract
The present invention provides afatinib, a preparation method therefor and an application thereof. The method comprises: by taking carbon tetrabromide and an organophosphorus compound as a condensation reagent, taking a dimethyl amino crotonic acid and/or dimethyl amino crotonic acid salt and N4-(3-chlorine-4-fluorine-phenyl)-7-(( S )-tetrahydrofuran-3-yloxy) quinazoline-4, 6-diamine as raw materials, performing a condensation reaction to generate the afatinib. According to the preparation method provided by the present invention, the carbon tetrabromide and the organophosphorus compound are taken as the condensation reagent, and the afatinib can be obtained by virtue of one-step condensation reaction. The process is simple, and during the process of preparing the afatinib, a selection range of the condensation reagent is expanded; and the reaction yield can be higher than 90%, and the product purity is higher than 95%.
Description
Technical field
The present invention relates to medicinal chemistry arts, particularly, the present invention relates to a kind of Ah method for Buddhist nun and its preparation method and application.
Background technology
Ah method is for Buddhist nun (Afatinib), it is a kind of anti cancer target medicine of innovation, i.e. oral target medicine of new generation, for the first kind in the whole world irreversibly (comprises four kinds of different cancer cells EGF-R ELISA in conjunction with ErbB family, as EGFR, HER2, ErbB3 and ErbB4) anti cancer target medicine, and then block more effectively and pointedly the signal of priming cancer cell growth, reduce or delay the hyperplasia of cancer cells.Ah method is used as first-line treatment medicine the many countries and regions in the U.S., Europe and Taiwan are granted for Buddhist nun, being applied to nonsmall-cell lung cancer (NSCLC) treatment with EGF-R ELISA (EGFR) mutated cancer cells, is oral target therapeutic agent once a day.
Ah method is researched and developed by German Boehringer Ingelheim company for Buddhist nun, through multinomial large-scale clinical verification, is chosen as breakthrough treatment by FDA.Ah method is gone on the market in the U.S. and Europe in 2013 for Buddhist nun, and trade name is respectively " Gilotrif " and " Giotrif "; Middle culture-commerce's name is respectively in Taiwan and Hong Kong " appropriate multiple gram " and " mark must reach ".
Ah method by suppressing the intracellular signaling of above-mentioned ErbB family, takes on critical role for preventing tumor growth and diffusion for Buddhist nun.Ah method is irreversibly combined with ErbB family receptors for the interaction energy of Buddhist nun, interrupts downstream information conduction, thus stops growth of cancer cells, and cancer cell specific induction of apoptosis (programmed death).Therefore, compare other targeted drugs, Ah method can provide for Buddhist nun and the characteristic that ErbB family receptors is irreversibly combined have more lastingly, selectivity, covalency and the Information Conduction that fully interrupts by cancer cells, thus bring unique anticancer therapy benefit, have more potentiality disinthibite wide class tumour cell increase, its curative effect is also more remarkable.
Ah method is N-[4-[(the chloro-4-fluorophenyl of 3-) is amino]-7-[[(3S)-tetrahydrochysene-3-furyl] oxygen base]-6-quinazolyl]-4-(dimethylamino)-2-butylene acid amides for its chemical name of Buddhist nun; 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 C
24h
25clFN
5o
3; Relative molecular weight is 485.9; CAS registration number is 439081-18-2, and structural formula is as follows:
At present, Ah method mainly contains following 3 kinds for the known route of synthesis of Buddhist nun:
Preparation method disclosed in US20050085495 is through 1 with diethylphosphoryl acetic acid, 1-carbonyl dimidazoles activates, with Ah method for Buddhist nun's intermediate N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, 6-diamine reactant, { [4-(the fluoro-phenyl amino of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen)-quinazoline-6-base carbamyl]-methyl } the di(2-ethylhexyl)phosphate ethyl ester obtained, there is Horner-Wadsworth-Emmons reaction in the dimethylamino acetal after being hydrolyzed by aqueous hydrochloric acid again, the Ah method of obtaining is for Buddhist nun.Adopt the method can create a large amount of phosphorus compounds larger to environmental hazard.
CN1277822 has disclosed Ah method a kind of for the synthetic method of Buddhist nun: bromo β-crotonic acid and oxalyl chloride are reacted; the acyl chlorides obtained and Ah method are for Buddhist nun's intermediate N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4; 6-diamines generation acidylate; add dimethylamine subsequently, the Ah method that obtains is for Buddhist nun.The method productive rate low (only having 50% at the most), needs in addition by column chromatography for separation, is not suitable for large-scale industrial production.
CN103755688 discloses by dimethylamino cronate hydrochlorate, reagent (1 is connected by acid amides, 1-carbonyl dimidazoles) activation after or chlorination (oxalyl chloride) after, Ah method is obtained for Buddhist nun with N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamine reactant.The method first just must can carry out follow-up condensation reaction by after dimethylamino cronate acid salt activating, add operation steps, and the productive rate of product is lower.
Therefore, in the art, expect that developing a kind of technological operation simply, through single step reaction obtains the method for Ah method for Buddhist nun, and expectation can obtain high yield and highly purified Ah method replaces Buddhist nun.
Summary of the invention
For the deficiencies in the prior art, the object of the present invention is to provide a kind of Ah method for Buddhist nun and its preparation method and application.Preparation method of the present invention utilizes carbon tetrabromide and organo phosphorous compounds as amide condensed reagent, and just can obtain Ah method for Buddhist nun by a step condensation reaction, technique is simple, and yield is high, and product purity is high.
For reaching this object, the present invention by the following technical solutions:
On the one hand, the invention provides the preparation method of a kind of Ah method for Buddhist nun, described method with carbon tetrabromide and organo phosphorous compounds for condensation reagent, with dimethylamino β-crotonic acid and/or dimethylamino cronate and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines is raw material, carry out condensation reaction, the Ah method that generates is for Buddhist nun.
In the present invention, make use of a kind of new condensation reagent (i.e. the combination of carbon tetrabromide and organo phosphorous compounds), realize dimethylamino β-crotonic acid and/or dimethylamino cronate and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, amide condensed reaction between 6-diamines, widen preparation Ah method for the range of choice to condensation reagent in Buddhist nun's process, reaction yield is high, and product purity is high.
In the present invention, carbon tetrabromide and organo phosphorous compounds must with the use of could as condensation reagents, in reaction process, carbon tetrabromide and organo phosphorous compounds form phosphonium salt, make dimethylamino β-crotonic acid and/or dimethylamino cronate and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, there is amide condensed reaction in 6-diamines, if only use wherein one can not play this effect.
In the preparation method of Ah method of the present invention for Buddhist nun, described organo phosphorous compounds is trialkyl phosphine or triphenylphosphine, triphenylphosphine.
Preferably, trialkyl phosphine is any one in trimethyl-phosphine, triethyl phosphine, tripropyl phosphine or tributylphosphine.
Preferably, described dimethylamino cronate is dimethylamino cronate hydrochlorate.
Ah method of the present invention comprises the following steps for the preparation method of Buddhist nun:
(1) by dimethylamino β-crotonic acid and/or dimethylamino cronate, N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, organic amine and carbon tetrabromide are dissolved in organic solvent, add organo phosphorous compounds under stirring, react;
(2) reaction terminates rear suction filtration, and filtrate is washed, and organic layer concentrates, and recrystallization obtains Ah method for Buddhist nun.
In the preparation method of Ah method of the present invention for Buddhist nun, described organic solvent is aprotic organic solvent, preferred methylene dichloride and/or trichloromethane.Because the activity of condensation reagent of the present invention (combination of carbon tetrabromide and organo phosphorous compounds) is higher, can react with protic solvent (as water, methyl alcohol etc.), therefore the present invention use aprotic organic solvent to ensure carbon tetrabromide and organo phosphorous compounds have greater activity, the efficiency that the present invention is reacted is higher.
In the preparation method of Ah method of the present invention for Buddhist nun, step (1) described dimethylamino β-crotonic acid and/or dimethylamino cronate and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 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.
Dimethylamino β-crotonic acid of the present invention and/or dimethylamino cronate and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines, refer to when in raw material only containing a kind of in dimethylamino β-crotonic acid and dimethylamino cronate time, then the ratio of this molar weight refers to dimethylamino β-crotonic acid or dimethylamino cronate and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines, if when using dimethylamino β-crotonic acid and dimethylamino cronate in raw material simultaneously, then the ratio of molar weight refers to amount sum and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4 of dimethylamino β-crotonic acid and dimethylamino cronate, the ratio of the molar weight of 6-diamines.
Preferably, step (1) described organic amine is the combination of any one or at least two kinds in diethylamine, triethylamine or quadrol, preferred triethylamine.
Preferably, the ratio of the molar weight of step (1) described organic amine and dimethylamino β-crotonic acid and/or dimethylamino cronate is (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) described carbon tetrabromide and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 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 object adding organic amine is in the present invention for reaction provides alkaline environment, when raw material is dimethylamino cronate hydrochlorate, organic amine is utilized hydrochloric part in raw material dimethylamino cronate hydrochlorate to be neutralized, obtain dimethylamino β-crotonic acid, to react with N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines.
In the preparation method of Ah method of the present invention for Buddhist nun, relative to 1gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, the consumption 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) described organo phosphorous compounds and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 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 organo phosphorous compounds in the present invention, have heat produce, in order to prevent overheated bring danger or produce side reaction, under agitation slowly add organo phosphorous compounds.
In the preparation method of Ah method of the present invention for Buddhist nun, 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, such as 30min, 35min, 40min, 45min, 50min, 55min, 60min, 65min, 70min, 75min, 80min, 85min or 90min, preferably 40 ~ 60min.
Preferably, the described simmer down to concentrating under reduced pressure of step (2).
Preferably, step (2) described recrystallization is for using recrystallisation from isopropanol.
As the preferred technical solution of the present invention, described Ah method comprises the following steps for the preparation method of Buddhist nun:
(1) will with N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.1): the dimethylamino β-crotonic acid of 1 and/or dimethylamino cronate, be (2 ~ 2.2) with the ratio of the molar weight of dimethylamino β-crotonic acid and/or dimethylamino cronate: the organic amine of 1 and with N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.1): the carbon tetrabromide of 1 is dissolved in organic solvent, add under stirring and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.1): the organo phosphorous compounds of 1, 20 ~ 30 DEG C of reaction 30 ~ 90min,
(2) reaction terminates rear suction filtration, and filtrate is washed, organic layer concentrating under reduced pressure, obtains Ah method for Buddhist nun with recrystallisation from isopropanol.
As the present invention's preferred technical scheme further, described Ah method comprises the following steps for the preparation method of Buddhist nun:
(1) will with N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.05): the dimethylamino β-crotonic acid of 1 and/or dimethylamino cronate, be (2 ~ 2.1) with the ratio of the molar weight of dimethylamino β-crotonic acid and/or dimethylamino cronate: the organic amine of 1 and with N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.05): the carbon tetrabromide of 1 is dissolved in aprotic organic solvent, add under stirring and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.05): the organo phosphorous compounds of 1, 20 ~ 25 DEG C of reaction 40 ~ 60min,
(2) reaction terminates rear suction filtration, and filtrate is washed, organic layer concentrating under reduced pressure, obtains Ah method for Buddhist nun with recrystallisation from isopropanol.
On the other hand, the invention provides Ah method that preparation method as described in relation to the first aspect prepares for Buddhist nun.
On the other hand, the invention provides Ah method of the present invention and prepare the application in anticancer targeting medicine for Buddhist nun.
Ah method of the present invention can be used as anti cancer target medicine for Buddhist nun, effectively and pointedly blocks the signal that priming cancer cell grows, reduces or delay the hyperplasia of cancer cells.
Relative to prior art, the present invention has following beneficial effect:
Preparation method of the present invention utilizes carbon tetrabromide and organo phosphorous compounds as condensation reagent, Ah method just can be obtained for Buddhist nun by a step condensation reaction, technique is simple, and widen preparation Ah method for the range of choice to condensation reagent in Buddhist nun's process, reaction yield can reach more than 90%, and product purity is more than 95%.
Embodiment
Technical scheme of the present invention is further illustrated below by embodiment.Those skilled in the art should understand, described embodiment is only help to understand the present invention, should not be considered as concrete restriction of the present invention.
embodiment 1
In the present embodiment, prepare Ah method by the following method for Buddhist nun, said method comprising the steps of:
By 24.3g dimethylamino cronate hydrochlorate, 55.0gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, 40.8mL triethylamine and 48.7g carbon tetrabromide are dissolved in dry 660mL methylene dichloride, 38.5g triphenylphosphine is slowly added under 20 DEG C of stirrings, after 45min, reaction terminates, suction filtration, filtrate washing (700mL × 2 time), organic layer is evaporated to dry, residue 200mL recrystallisation from isopropanol obtains 64.2g Ah method for Buddhist nun, molar yield is 90.1%, and product purity is 97%.
1hNMR (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]+, illustrate that material prepared by the present embodiment is for Ah method is for Buddhist nun.
embodiment 2
In the present embodiment, prepare Ah method by the following method for Buddhist nun, said method comprising the steps of:
By 50.1g dimethylamino cronate hydrochlorate, 108.0gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, 84.2mL triethylamine and 100.3g carbon tetrabromide are dissolved in dry 1944mL methylene dichloride, add 79.4g triphenylphosphine under 25 DEG C of stirrings in batches, after 60min, reaction terminates suction filtration, filtrate washing (1900mL × 2 time), organic layer is evaporated to dry, residue 390mL recrystallisation from isopropanol obtains 130.2g Ah method for Buddhist nun, molar yield is 93%, and product purity is 98%.
Warp
1hNMR and LC-MS (ESI): 486.2 [M+H]+, illustrate that material prepared by the present embodiment is for Ah method is for Buddhist nun.
Embodiment 3
In the present embodiment, prepare Ah method by the following method for Buddhist nun, said method comprising the steps of:
By 39.0g dimethylamino β-crotonic acid, 108.0gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, 40.5mL quadrol and 100.3g carbon tetrabromide are dissolved in dry 1944mL methylene dichloride, add 79.4g triphenylphosphine under 25 DEG C of stirrings in batches, after 60min, reaction terminates suction filtration, filtrate washing (1900mL × 2 time), organic layer is evaporated to dry, residue 390mL recrystallisation from isopropanol obtains 126g Ah method for Buddhist nun, molar yield is 90%, and product purity is 95%.
Warp
1hNMR and LC-MS (ESI): 486.2 [M+H]+, illustrate that material prepared by the present embodiment is for Ah method is for Buddhist nun.
embodiment 4
By 52.7g dimethylamino cronate hydrochlorate, 117.0gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, 88.6mL triethylamine and 105.6g carbon tetrabromide are dissolved in dry 1870mL methylene dichloride, 83.5g trimethyl-phosphine is slowly added under 23 DEG C of stirrings, after 65min, reaction terminates suction filtration, filtrate washing (1800mL × 2 time), organic layer is evaporated to dry, residue 455mL recrystallisation from isopropanol obtains 138.0g Ah method for Buddhist nun, molar yield is 91%, and product purity is 96%.
Warp
1hNMR and LC-MS (ESI): 486.1 [M+H]+, illustrate that material prepared by the present embodiment is for Ah method is for Buddhist nun.
embodiment 5
In the present embodiment, prepare Ah method by the following method for Buddhist nun, said method comprising the steps of:
By 26.7g dimethylamino cronate hydrochlorate, 55.0gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, 49.1mL diethylamine and 53.5g carbon tetrabromide are dissolved in dry 1100mL methylene dichloride, 42.3g triphenylphosphine is slowly added under 20 DEG C of stirrings, after 30min, reaction terminates, suction filtration, filtrate washing (800mL × 2 time), organic layer is evaporated to dry, residue 200mL recrystallisation from isopropanol obtains 64.2g Ah method for Buddhist nun, molar yield is 90%, and product purity is 97%.
Warp
1hNMR and LC-MS (ESI): 486.0 [M+H]+, illustrate that material prepared by the present embodiment is for Ah method is for Buddhist nun.
embodiment 6
In the present embodiment, prepare Ah method by the following method for Buddhist nun, said method comprising the steps of:
By 53g dimethylamino cronate hydrochlorate, 120.0gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, 93mL triethylamine and 111.4g carbon tetrabromide are dissolved in dry 1800mL methylene dichloride, 25.5g trimethyl-phosphine is slowly added under 25 DEG C of stirrings, after 90min, reaction terminates suction filtration, filtrate washing (1800mL × 2 time), organic layer is evaporated to dry, residue 400mL recrystallisation from isopropanol obtains 140g Ah method for Buddhist nun, molar yield is 90%, and product purity is 95%.
Warp
1hNMR and LC-MS (ESI): 486.1 [M+H]+, illustrate that material prepared by the present embodiment is for Ah method is for Buddhist nun.
embodiment 7
In the present embodiment, prepare Ah method by the following method for Buddhist nun, said method comprising the steps of:
By 25.8g dimethylamino β-crotonic acid and 19.86g dimethylamino cronate hydrochlorate, 120.0gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, 6-diamines, 93mL triethylamine and 111.4g carbon tetrabromide are dissolved in dry 1800mL methylene dichloride, 67.9g tributylphosphine is slowly added under 25 DEG C of stirrings, after 90min, reaction terminates suction filtration, filtrate washing (1800mL × 2 time), organic layer is evaporated to dry, residue 400mL recrystallisation from isopropanol obtains 140g Ah method for Buddhist nun, molar yield is 90%, product purity is 96%.
Warp
1hNMR and LC-MS (ESI): 486.1 [M+H]+, illustrate that material prepared by the present embodiment is for Ah method is for Buddhist nun.
embodiment 8
In the present embodiment, prepare Ah method by the following method for Buddhist nun, said method comprising the steps of:
By 52.4g dimethylamino cronate hydrochlorate, 108.0gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, 54.7mL quadrol and 103.1g carbon tetrabromide are dissolved in dry 1080mL methylene dichloride, add 80.8g triphenylphosphine under 25 DEG C of stirrings in batches, after 40min, reaction terminates suction filtration, filtrate washing (1900mL × 2 time), organic layer is evaporated to dry, residue 390mL recrystallisation from isopropanol obtains 130.2g Ah method for Buddhist nun, molar yield is 93%, and product purity is 97%.
Warp
1hNMR and LC-MS (ESI): 486.1 [M+H]+, illustrate that material prepared by the present embodiment is for Ah method is for Buddhist nun.
embodiment 9
In the present embodiment, prepare Ah method by the following method for Buddhist nun, said method comprising the steps of:
By 51.5g dimethylamino cronate hydrochlorate, 108.0gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, 94.7mL triethylamine and 103.1g carbon tetrabromide are dissolved in dry 1080mL methylene dichloride, add 80.8g triphenylphosphine under 25 DEG C of stirrings in batches, after 40min, reaction terminates suction filtration, filtrate washing (1900mL × 2 time), organic layer is evaporated to dry, residue 390mL recrystallisation from isopropanol obtains 128.7g Ah method for Buddhist nun, molar yield is 92%, and product purity is 96%.
Warp
1hNMR and LC-MS (ESI): 486.2 [M+H]+, illustrate that material prepared by the present embodiment is for Ah method is for Buddhist nun.
comparative example 1
This comparative example difference from Example 1 is, in reaction process, for condensation reagent, only add the carbon tetrabromide identical with embodiment 1 consumption, and do not add any organo phosphorous compounds, all the other raw materials and raw material dosage and reaction conditions all identical with embodiment 1.Warp
1hNMR and LC-MS (ESI) characterizes discovery, and this comparative example can not get Ah method for Buddhist nun at all, illustrates that carbon tetrabromide can not make raw material generation condensation reaction as condensation reagent separately, only has to coordinate competence exertion with organo phosphorous compounds it acts on.
comparative example 2
This comparative example difference from Example 1 is, in reaction process, for condensation reagent, only adds the triphenylphosphine identical with embodiment 1 consumption, and does not add carbon tetrabromide, all the other raw materials and raw material dosage and reaction conditions all identical with embodiment 1.Warp
1hNMR and LC-MS (ESI) characterizes discovery, this comparative example can not get Ah method for Buddhist nun at all, illustrate that triphenylphosphine can not make raw material generation condensation reaction as condensation reagent separately, triphenylphosphine is changed into other organo phosphorous compoundss, and not adding carbon tetrabromide, the Ah method that still can not get is for Buddhist nun.
comparative example 3
This comparative example difference from Example 2 is, by carbon tetrabromide and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is set as 0.9:1 and 1.2:1 (namely adding 86g carbon tetrabromide and 114.6g carbon tetrabromide respectively) respectively, all the other raw materials and raw material dosage and reaction conditions all identical with embodiment 2, carry out the preparation of Ah method for Buddhist nun respectively.At carbon tetrabromide and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the Ah method that the ratio of the molar weight of 6-diamines obtains when being respectively 0.9:1 and 1.2:1 is respectively 70% and 72% for the molar yield of Buddhist nun, and product purity is respectively 73% and 75%.
comparative example 4
This comparative example difference from Example 3 is, by triphenylphosphine and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is set as 0.9:1 and 1.2:1 (namely adding 67.9g triphenylphosphine and 90.5g triphenylphosphine respectively) respectively, all the other raw materials and raw material dosage and reaction conditions all identical with embodiment 3, carry out the preparation of Ah method for Buddhist nun respectively.At triphenylphosphine and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, when the ratio of the molar weight of 6-diamines is set as 0.9:1 and 1.2:1 respectively, the Ah method obtained is 71% and 73% for the molar yield of Buddhist nun respectively, and product purity is respectively 75% and 78%.
As seen from the above embodiment, the method for the invention has on the one hand expanded the range of choices of amide condensed reagent, on the other hand by " one kettle way " reaction, simplifies the preparation method of Ah method for Buddhist nun, prepare simultaneously high quality, high yield Ah method for Buddhist nun.Ah method prepared by the present invention can be used as anti cancer target medicine for Buddhist nun, effectively and pointedly blocks the signal that priming cancer cell grows, reduces or delay the hyperplasia of cancer cells.
Applicant states, by above-described embodiment, the present invention illustrates that Ah method of the present invention is for Buddhist nun and its preparation method and application, but the present invention is not limited to above-described embodiment, does not namely mean that the present invention must rely on above-described embodiment and could implement.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of ancillary component, the concrete way choice etc. of each raw material of product of the present invention, all drops within protection scope of the present invention and open scope.
Claims (10)
1. an Ah method is for the preparation method of Buddhist nun, it is characterized in that, described method with carbon tetrabromide and organo phosphorous compounds for condensation reagent, with dimethylamino β-crotonic acid and/or dimethylamino cronate and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines is raw material, carry out condensation reaction, the Ah method that generates is for Buddhist nun.
2. preparation method according to claim 1, is characterized in that, described organo phosphorous compounds is trialkyl phosphine or triphenylphosphine, triphenylphosphine;
Preferably, described trialkyl phosphine is any one in trimethyl-phosphine, triethyl phosphine, tripropyl phosphine or tributylphosphine;
Preferably, described dimethylamino cronate is dimethylamino cronate hydrochlorate.
3. preparation method according to claim 1 and 2, is characterized in that, described preparation method comprises the following steps:
(1) by dimethylamino β-crotonic acid and/or dimethylamino cronate, N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, organic amine and carbon tetrabromide are dissolved in organic solvent, add organo phosphorous compounds under stirring, react;
(2) reaction terminates rear suction filtration, and filtrate is washed, and organic layer concentrates, and recrystallization obtains Ah method for Buddhist nun.
4. preparation method according to claim 3, is characterized in that, step (1) described organic solvent is aprotic organic solvent, preferred methylene dichloride and/or trichloromethane.
5. the preparation method according to claim 3 or 4, it is characterized in that, step (1) described dimethylamino β-crotonic acid and/or dimethylamino cronate and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.1): 1, preferably (1 ~ 1.05): 1;
Preferably, step (1) described organic amine is the combination of any one or at least two kinds in diethylamine, triethylamine or quadrol, preferred triethylamine;
Preferably, the ratio of the molar weight of step (1) described organic amine and dimethylamino β-crotonic acid and/or dimethylamino cronate is (2 ~ 2.2): 1, preferably (2 ~ 2.1): 1;
Preferably, step (1) described carbon tetrabromide and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.1): 1, preferably (1 ~ 1.05): 1.
6. the preparation method according to any one of claim 3-5, it is characterized in that, relative to 1gN4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4,6-diamines, the consumption of step (1) described organic solvent is 10 ~ 20mL, preferably 12 ~ 18mL;
Preferably, step (1) described organo phosphorous compounds and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.1): 1, preferably (1 ~ 1.05): 1.
7. the preparation method according to any one of claim 3-6, is characterized in that, the temperature of step (1) described reaction is 20 ~ 30 DEG C, preferably 20 ~ 25 DEG C;
Preferably, the time of step (1) described reaction is 30 ~ 90min, preferably 40 ~ 60min;
Preferably, the described simmer down to concentrating under reduced pressure of step (2);
Preferably, step (2) described recrystallization is for using recrystallisation from isopropanol.
8. the preparation method according to any one of claim 3-7, is characterized in that, described preparation method comprises the following steps:
(1) will with N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.1): the dimethylamino β-crotonic acid of 1 and/or dimethylamino cronate, be (2 ~ 2.2) with the ratio of the molar weight of dimethylamino β-crotonic acid and/or dimethylamino cronate: the organic amine of 1 and with N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.1): the carbon tetrabromide of 1 is dissolved in organic solvent, add under stirring and N4-(the fluoro-phenyl of the chloro-4-of 3-)-7-((S)-tetrahydrofuran (THF)-3-base oxygen) quinazoline-4, the ratio of the molar weight of 6-diamines is (1 ~ 1.1): the organo phosphorous compounds of 1, 20 ~ 30 DEG C of reaction 30 ~ 90min,
(2) reaction terminates rear suction filtration, and filtrate is washed, organic layer concentrating under reduced pressure, obtains Ah method for Buddhist nun with recrystallisation from isopropanol.
9. the Ah method that the preparation method according to any one of claim 1-8 prepares is for Buddhist nun.
10. Ah method according to claim 9 is preparing the application in anticancer targeting medicine for Buddhist nun.
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| 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 |
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| 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 |
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