CN111763214B - Preparation method of icotinib - Google Patents

Preparation method of icotinib Download PDF

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CN111763214B
CN111763214B CN202010794011.7A CN202010794011A CN111763214B CN 111763214 B CN111763214 B CN 111763214B CN 202010794011 A CN202010794011 A CN 202010794011A CN 111763214 B CN111763214 B CN 111763214B
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amino
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difluoroquinazoline
icotinib
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CN111763214A (en
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张晓红
吕习周
陆建刚
张慧慧
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Suzhou Fushilai Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

A preparation method of icotinib comprises the following steps: fully mixing 2-amino-4, 5-difluorobenzoic acid with a solution of an amidation reagent, adding a catalyst, and carrying out amidation reaction; dissolving the obtained 2-amino-4, 5-difluorobenzamide and a cyclization reagent in a solvent, and performing cyclization reaction at high temperature; carrying out chlorination reaction on the obtained 6, 7-difluoro-3, 4-dihydroquinazoline-4-ketone and a chlorination reagent in a solvent system; carrying out condensation reaction on the obtained 4-chloro-6, 7-difluoroquinazoline and 3-ethynylaniline in an alkali reagent and solvent system; and carrying out etherification reaction on the obtained 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline and triethylene glycol in an alkali reagent and a solvent system to obtain the Icotinib. The impurities are less and controllable, the next reaction can be directly carried out, the operation is simplified, and good yield can be obtained in each step; the process flow is simplified, and the safety and the environmental protection are guaranteed.

Description

Preparation method of icotinib
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of icotinib.
Background
Icotinib (Icotiniib) is an innovative anti-tumor targeted therapy drug independently developed by Bida pharmaceutical industry in Zhejiang in China, is the first small-molecule anti-tumor drug with independent intellectual property rights in China, and an Icotinib hydrochloride tablet is approved by the national food and drug administration in 2011 and is used for treating advanced non-small cell lung cancer (NSCLC). The chemical name of icotinib is 4- [ (3-ethynylphenyl) amino ] -6,7-benzo-12-crown-4 quinazoline, the English chemical name is 4- [ (3-ethylphenyl) amino ] -6, 7-benzol-12-crown-4-quinazoline, the trade name is kaimer (Conmana), and the structural formula is as follows:
Figure BDA0002624825520000011
icotinib is a high-efficiency and specific epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and has obvious inhibition effects on FGFR, PDGFR and VEGFR besides the EGFR-TKIs. Compared with gefitinib (Gifitinib) and Erlotinib (Erlotinib), the Erlotinib is similar in the aspects of action mechanism, indications, curative effect and the like on the chemical structure and molecular level, but has the characteristic of lowest toxicity, and the cyclic dodecacrown ether side chain structure and high selectivity on EGFR-TKI are the basis of good safety, so that the Erlotinib has unique advantages and positions in the new antitumor drug market.
Regarding the preparation method of the icotinib, different process routes reported in the prior literatures and patents relate to the construction of a dodecacrown ether structure and the construction of a quinazoline ring, and the icotinib has characteristics and advantages and disadvantages.
Route one (patent CN1305860C) is the original patent route of Berda pharmaceutical industry, 2-amino-4, 5-dimethoxybenzoic acid is used as an initial raw material, a quinazoline structure is obtained through cyclization, then chlorination and arylamine condensation are carried out, finally a dodecacrown ether structure is constructed, and Icotinib is generated, wherein the synthetic route is shown as follows:
Figure BDA0002624825520000012
Figure BDA0002624825520000021
and the second route is based on the first route, the access structure of the condensation reaction with arylamine is changed, namely after cyclization and chlorination, the grafting is firstly performed with m-bromoaniline for nucleophilic docking, and after construction of dodecacrown ether is completed, the coupling reaction is finally performed with ethynyl trimethylsilane to obtain the Icotinib, which is shown as follows:
Figure BDA0002624825520000022
route three (patents CN101878218B, CN102911179B, CN103254204B, CN104530061B, and CN104592242B) is a patent route disclosed in the beda pharmaceutical industry, and the method uses triethylene glycol as a starting material, and reacts with p-toluenesulfonyl chloride to obtain dihydroxy protection, and then the dihydroxy protection reacts with ethyl 3, 4-dihydroxybenzoate to construct a dodecacrown ether structure, and further the reaction is performed by nitration, reduction, cyclization, chlorination, and condensation to obtain icotinib, as shown below:
Figure BDA0002624825520000031
route four (patents CN104024262B and CN105237510A) is another new patent route disclosed in the beda pharmaceutical industry, in which triethylene glycol is used as a starting material, hydroxyl group is protected, and condensed with 3, 4-dihydroxybenzene acetonitrile to construct dodecacrown ether, then nitration, iron powder reduction, condensation with N, N-dimethylformamide dimethyl acetal, and then reaction with m-aminophenylacetylene to obtain icotinib, compared with the process of route three, although the cyclization reaction does not involve a chlorination process, the use of highly toxic reagents such as phosphine oxychloride and the like can be avoided, the yield of the cyclization step is reduced, the cost of the whole process route is increased, and the synthetic route is as follows:
Figure BDA0002624825520000032
the synthesis route of the icotinib carries out hydroxyl protection on the initial raw material in advance, so that the reaction steps are increased, the operation is complicated and tedious, and the efficiency is not improved and the cost is reduced. In order to search for a more effective and simple way for preparing the icotinib, the method has positive significance for exploring a preparation method of the icotinib which has the advantages of short process flow, simple operation, low cost, safety and environmental protection and is suitable for industrial production, and the technical scheme to be introduced below is generated under the background.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the preparation method of the icotinib, which has the advantages of reasonable process route, simple operation, easily obtained reagents, low preparation cost and good safety to the environment.
The invention aims to achieve the aim that the preparation method of the icotinib comprises the following steps:
(1) fully mixing 2-amino-4, 5-difluorobenzoic acid with a solution of an amidation reagent, adding a catalyst, and carrying out amidation reaction to obtain 2-amino-4, 5-difluorobenzamide, wherein the reaction formula is as follows:
Figure BDA0002624825520000041
(2) dissolving 2-amino-4, 5-difluorobenzamide and a cyclization reagent in a solvent, and carrying out cyclization reaction at high temperature to obtain 6, 7-difluoro-3, 4-dihydroquinazolin-4-one, wherein the reaction formula is as follows:
Figure BDA0002624825520000042
the cyclization reagent is trimethyl orthoformate, triethyl orthoformate, formic acid, formamide, ammonium formate or formamidine;
(3) carrying out chlorination reaction on 6, 7-difluoro-3, 4-dihydroquinazoline-4-ketone and a chlorinating agent in a solvent system to obtain 4-chloro-6, 7-difluoroquinazoline, wherein the reaction formula is as follows:
(4) carrying out condensation reaction on 4-chloro-6, 7-difluoroquinazoline and 3-ethynylaniline in an alkali reagent and a solvent system to obtain 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline, wherein the reaction formula is as follows:
Figure BDA0002624825520000044
(5)4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline and triethylene glycol are subjected to etherification reaction in an alkali reagent and solvent system to obtain Icotinib (Icotinib), and the reaction formula is as follows:
Figure BDA0002624825520000051
in a specific embodiment of the invention, the molar ratio of the 2-amino-4, 5-difluorobenzoic acid, the amidation reagent and the catalyst in the step (1) is 1.0: 3.0-10.0: 0.01-0.10; the amidation reaction is carried out in a high-pressure reaction kettle by heating, the reaction temperature is 70-100 ℃, and the reaction time is 6-24 hours.
In another specific embodiment of the invention, the solution of amidation agent is ammonia water, an ethanol solution of ammonia or a methanol solution of ammonia; the catalyst is copper sulfate, cupric nitrate, cupric acetate, cupric chloride, cupric bromide, cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, cuprous acetate, copper trifluoromethanesulfonate, cupric propionate, copper isobutyrate or copper powder.
In another specific embodiment of the present invention, the molar ratio of the 2-amino-4, 5-difluorobenzamide and the cyclizing reagent in the step (2) is 1.0: 1.0-1.5; the temperature of the cyclization reaction is 80-125 ℃, and the reaction time is 6-24 h.
In still another embodiment of the present invention, the solvent in step (2) is methanol, ethanol, isopropanol or n-propanol.
In still another specific embodiment of the present invention, the molar ratio of the 6, 7-difluoro-3, 4-dihydroquinazolin-4-one to the chlorinating agent in step (3) is 1.0: 1.0-1.6; the temperature of the chlorination reaction is 30-100 ℃, and the reaction time is 3-8 h.
In a more specific embodiment of the present invention, the chlorinating agent in step (3) is phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosphorus pentachloride or phosphorus trichloride; the solvent is tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide, N-diethylformamide, 1, 4-dioxane or acetonitrile.
In a further specific embodiment of the present invention, the molar ratio of the 4-chloro-6, 7-difluoroquinazoline, the 3-ethynylaniline, and the alkaline reagent in step (4) is 1.0: 1.3-1.8: 1.8-2.5; the condensation reaction is carried out at the temperature of 50-100 ℃ for 6-12 h; the alkali reagent is sodium hydroxide, potassium carbonate, sodium carbonate or cesium carbonate; the solvent is dichloromethane, 1, 2-dichloroethane, chloroform, toluene, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, methyl tert-butyl ether, acetonitrile or 1, 4-dioxane.
In still another specific embodiment of the present invention, the molar ratio of the 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline and the triethylene glycol to the alkali agent in the step (5) is 1.0: 1.0 to 1.3: 1.3 to 1.8; the temperature of the etherification reaction is 60-100 ℃, and the reaction time is 4-24 h; the solvent is dichloromethane, 1, 2-dichloroethane, chloroform, toluene, N-dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether, 1, 4-dioxane, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran.
In yet another specific embodiment of the present invention, the alkali agent is metallic sodium, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, potassium isopropoxide or potassium tert-pentoxide.
The technical scheme provided by the invention has the following technical effects: firstly, because only conventional post-treatment and purification are carried out after the reaction of each step is finished without the purification of a chromatographic column, impurities are less and controllable, and the next reaction can be directly carried out, the operation is simplified, and simultaneously, good yield can be obtained in each step; secondly, the starting raw materials and the used reagents of the process route are easy to obtain, the technical scheme of the synthesis reaction is reasonable, the process flow is obviously simplified, the safety and the environmental protection are guaranteed, the use requirements of the raw material medicines can be met by mass production, and the method is suitable for the industrial amplification production requirements.
Detailed Description
The following non-limiting detailed description of the present invention is provided in connection with several preferred embodiments.
Example 1:
(1) preparation of 2-amino-4, 5-difluorobenzamide:
adding 2-amino-4, 5-difluorobenzoic acid (50.0g,0.29mol) and 28% ammonia water solution (60mL,0.90mol) into a 2L high-pressure reaction kettle, fully mixing, adding copper sulfate (0.5g,3.1mmol), sealing the reaction kettle, heating to 70 ℃ for reaction for 24 hours, cooling to room temperature, decompressing and rotary-steaming the reaction mixture to dryness, extracting dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, decompressing and rotary-steaming to dryness, recrystallizing the crude product with an ethyl acetate-petroleum ether mixed solvent to obtain 2-amino-4, 5-difluorobenzamide, and obtaining an off-white solid (44.0g), wherein the yield is 89%, and the reaction formula in the step is as follows:
Figure BDA0002624825520000061
(2) preparation of 6, 7-difluoro-3, 4-dihydroquinazolin-4-one:
dissolving 2-amino-4, 5-difluorobenzamide (44.0g,0.26mol) in methanol (700mL), cooling in an ice bath, slowly adding trimethyl orthoformate (27.5g,0.26mol), reacting at 80 ℃ for 24h, cooling to room temperature, reducing pressure and carrying out rotary evaporation to dryness, extracting dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, reducing pressure and carrying out rotary evaporation to dryness, recrystallizing a crude product by using an ethyl acetate-petroleum ether mixed solvent to obtain 6, 7-difluoro-3, 4-dihydroquinazolin-4-one, an off-white solid (42.0g), wherein the yield is 90%, and the reaction formula in the step is as follows:
Figure BDA0002624825520000062
(3) preparation of 4-chloro-6, 7-difluoroquinazoline:
dissolving 6, 7-difluoro-3, 4-dihydroquinazolin-4-one (42.0g,0.23mol) in tetrahydrofuran (600mL), cooling in ice bath, slowly adding phosphorus oxychloride (36.0g,0.23mol), reacting at 30 ℃ for 8h, cooling to room temperature, carrying out reduced pressure rotary evaporation to dryness, extracting with dichloromethane, washing with saline water and saturated sodium bicarbonate solution in sequence, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the obtained crude product with ethyl acetate-petroleum ether mixed solvent to obtain 4-chloro-6, 7-difluoroquinazoline, a white-like solid (43.0g), wherein the yield is 93%, and the reaction formula in the step is as follows:
Figure BDA0002624825520000071
(4) preparation of 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline:
4-chloro-6, 7-difluoroquinazoline (43.0g,0.21mol) was dissolved in dichloromethane (600mL), cooled in an ice bath, 3-ethynylaniline (33.0g,0.28mol) and sodium hydroxide (16g,0.4mol) were slowly added, reacted at 50 ℃ for 12h, cooled to room temperature, rotary evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and rotary evaporated to dryness under reduced pressure, the resulting crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to give 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline, as a white to pale yellow solid (55.0g), 91% yield, according to the reaction formula:
Figure BDA0002624825520000072
(5) preparation of icotinib:
dissolving 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline (55.0g,0.20mol) in dichloromethane (600mL), cooling in an ice bath, slowly adding triethylene glycol (30.0g,0.20mol) and sodium hydride (6.0g,0.25mol), reacting at 60 ℃ for 24h, cooling to room temperature, carrying out reduced pressure rotary evaporation to dryness, extracting dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the obtained crude product with an ethyl acetate-petroleum ether mixed solvent to obtain Icotinib, an off-white solid (73.0g), wherein the yield is 95%, and the reaction formula in the step is as follows:
Figure BDA0002624825520000073
example 2:
(1) preparation of 2-amino-4, 5-difluorobenzamide:
adding 2-amino-4, 5-difluorobenzoic acid (80.0g,0.46mol) and a 15% ammonia ethanol solution (340mL,2.40mol) into a 2L high-pressure reaction kettle, fully mixing, adding copper chloride (3.0g,22.3mmol), sealing the reaction kettle, heating to 90 ℃ for reaction for 9 hours, cooling to room temperature, carrying out reduced pressure rotary evaporation on the reaction mixture until the reaction mixture is dry, extracting dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation until the reaction mixture is dry, and recrystallizing a crude product by using an ethyl acetate-petroleum ether mixed solvent to obtain 2-amino-4, 5-difluorobenzamide, a white-like solid (70.0g) and the yield is 88%;
(2) preparation of 6, 7-difluoro-3, 4-dihydroquinazolin-4-one:
dissolving 2-amino-4, 5-difluorobenzamide (70.0g,0.41mol) in ethanol (1000mL), cooling in an ice bath, slowly adding triethyl orthoformate (78.0g,0.53mol), reacting at 100 ℃ for 12h, cooling to room temperature, carrying out reduced pressure rotary evaporation to dryness, extracting with dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing a crude product with an ethyl acetate-petroleum ether mixed solvent to obtain 6, 7-difluoro-3, 4-dihydroquinazolin-4-one as a white-like solid (66.0g), wherein the yield is 89%;
(3) preparation of 4-chloro-6, 7-difluoroquinazoline:
dissolving 6, 7-difluoro-3, 4-dihydroquinazolin-4-one (66.0g,0.36mol) in N, N-dimethylformamide (1000mL), cooling in ice bath, slowly adding phosphorus pentachloride (100.0g,0.48mol), reacting at 100 ℃ for 3h, cooling to room temperature, carrying out reduced pressure rotary evaporation to dryness, extracting with dichloromethane, washing with saline solution and saturated sodium bicarbonate solution in sequence, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the obtained crude product with ethyl acetate-petroleum ether mixed solvent to obtain 4-chloro-6, 7-difluoroquinazoline, white-like solid (63.0g), and obtaining the yield of 87%;
(4) preparation of 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline:
dissolving 4-chloro-6, 7-difluoroquinazoline (63.0g,0.31mol) in toluene (1000mL), cooling in an ice bath, slowly adding 3-ethynylaniline (56.0g,0.48mol) and potassium hydroxide (35.0g,0.62mol), reacting at 90 ℃ for 9h, cooling to room temperature, carrying out reduced pressure rotary evaporation to dryness, extracting with dichloromethane, washing with brine, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the obtained crude product with an ethyl acetate-petroleum ether mixed solvent to obtain 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline, which is white-like to light yellow solid (82.0g) with the yield of 93%;
(5) preparation of icotinib:
4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline (82.0g,0.29mol) was dissolved in toluene (1000mL), cooled in an ice bath, slowly added with triethylene glycol (52.0g,0.35mol) and potassium tert-butoxide (58.0g,0.52mol), reacted at 100 ℃ for 4h, cooled to room temperature, evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and the resulting crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to give Icotinib as an off-white solid (102.0g) in 89% yield.
Since the reaction formulae of steps (1) to (5) of example 2 are the same as those of steps (1) to (5) of example 1, respectively, they are omitted.
Example 3:
(1) preparation of 2-amino-4, 5-difluorobenzamide:
adding 2-amino-4, 5-difluorobenzoic acid (120.0g,0.69mol) and a 15% ammonia methanol solution (1020mL,6.92mol) into a 2L high-pressure reaction kettle, fully mixing, adding cuprous bromide (9.5g,66.3mmol), sealing the reaction kettle, heating to 100 ℃ for reaction for 6 hours, cooling to room temperature, carrying out reduced pressure rotary evaporation on the reaction mixture until the reaction mixture is dry, extracting dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation until the reaction mixture is dry, and recrystallizing a crude product by using an ethyl acetate-petroleum ether mixed solvent to obtain 2-amino-4, 5-difluorobenzamide, wherein the white-like solid is light yellow solid (113.0g), and the yield is 95%;
(2) preparation of 6, 7-difluoro-3, 4-dihydroquinazolin-4-one:
dissolving 2-amino-4, 5-difluorobenzamide (113.0g,0.66mol) in isopropanol (1800mL), cooling in an ice bath, slowly adding formic acid (45.0g,0.98mol), reacting at 125 ℃ for 6h, cooling to room temperature, carrying out reduced pressure rotary evaporation to dryness, extracting with dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing a crude product with an ethyl acetate-petroleum ether mixed solvent to obtain 6, 7-difluoro-3, 4-dihydroquinazolin-4-one as a white to pale yellow solid (108.0g), wherein the yield is 90%;
(3) preparation of 4-chloro-6, 7-difluoroquinazoline:
dissolving 6, 7-difluoro-3, 4-dihydroquinazolin-4-one (108.0g,0.59mol) in N, N-dimethylformamide (1400mL), cooling in ice bath, slowly adding thionyl chloride (112.0g,0.94mol), reacting at 90 ℃ for 5h, cooling to room temperature, carrying out reduced pressure rotary evaporation to dryness, extracting with dichloromethane, washing with saline and saturated sodium bicarbonate solution in sequence, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the obtained crude product with ethyl acetate-petroleum ether mixed solvent to obtain 4-chloro-6, 7-difluoroquinazoline which is white-like to light yellow solid (106.0g), wherein the yield is 0.89%;
(4) preparation of 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline:
dissolving 4-chloro-6, 7-difluoroquinazoline (106.0g,0.53mol) in 1, 2-dichloroethane (1300mL), cooling in an ice bath, slowly adding 3-ethynylaniline (111.0g,0.95mol) and potassium carbonate (182.0g,1.32mol), reacting at 100 ℃ for 6h, cooling to room temperature, carrying out reduced pressure rotary evaporation to dryness, extracting with dichloromethane, washing with brine, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the obtained crude product with an ethyl acetate-petroleum ether mixed solvent to obtain 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline, which is off-white to light yellow solid (140.0g), wherein the yield is 94%;
(5) preparation of icotinib:
4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline (140.0g,0.50mol) is dissolved in 1, 2-dichloroethane (1300mL), cooled in an ice bath, slowly added with triethylene glycol (97.0g,0.65mol) and sodium ethoxide (60.0g,0.88mol), reacted at 80 ℃ for 14h, cooled to room temperature, reduced pressure rotary evaporated to dryness, extracted with dichloromethane, washed with brine, dried with anhydrous sodium sulfate, reduced pressure rotary evaporated to dryness, and the obtained crude product is recrystallized by an ethyl acetate-petroleum ether mixed solvent to obtain Icotinib, quasi white (175.0g) with yield of 90%.
Since the reaction formulae of steps (1) to (5) of example 3 are the same as those of steps (1) to (5) of example 1, respectively, they are omitted.

Claims (10)

1. A preparation method of icotinib is characterized by comprising the following steps:
(1) fully mixing 2-amino-4, 5-difluorobenzoic acid with a solution of an amidation reagent, adding a catalyst, and carrying out amidation reaction to obtain 2-amino-4, 5-difluorobenzamide;
(2) dissolving 2-amino-4, 5-difluorobenzamide and a cyclizing reagent in a solvent, and performing cyclization reaction at high temperature to obtain 6, 7-difluoro-3, 4-dihydroquinazolin-4-one, wherein the cyclizing reagent is trimethyl orthoformate, triethyl orthoformate, formic acid, formamide, ammonium formate or formamidine;
(3) carrying out chlorination reaction on 6, 7-difluoro-3, 4-dihydroquinazoline-4-ketone and a chlorinating agent in a solvent system to obtain 4-chloro-6, 7-difluoroquinazoline;
(4) carrying out condensation reaction on 4-chloro-6, 7-difluoroquinazoline and 3-ethynylaniline in an alkali reagent and a solvent system to obtain 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline;
(5)4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline and triethylene glycol are subjected to etherification reaction in an alkali reagent and a solvent system to obtain the Icotinib.
2. The method for preparing icotinib, according to claim 1, characterized in that the molar ratio of 2-amino-4, 5-difluorobenzoic acid, amidation reagent and catalyst in step (1) is 1.0: 3.0-10.0: 0.01-0.10; the amidation reaction is carried out in a high-pressure reaction kettle by heating, the reaction temperature is 70-100 ℃, and the reaction time is 6-24 hours.
3. The method according to claim 1 or 2, wherein the solution of the amidation agent is an aqueous ammonia solution, an ethanol solution of ammonia, or a methanol solution of ammonia; the catalyst is copper sulfate, cupric nitrate, cupric acetate, cupric chloride, cupric bromide, cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, cuprous acetate, copper trifluoromethanesulfonate, cupric propionate, copper isobutyrate or copper powder.
4. The method according to claim 1, wherein the molar ratio of the 2-amino-4, 5-difluorobenzamide to the cyclizing reagent in step (2) is 1.0: 1.0-1.5; the temperature of the cyclization reaction is 80-125 ℃, and the reaction time is 6-24 h.
5. The method according to claim 1 or 4, wherein the solvent in step (2) is methanol, ethanol, isopropanol or n-propanol.
6. The method for preparing icotinib, according to claim 1, characterized in that the molar ratio of 6, 7-difluoro-3, 4-dihydroquinazolin-4-one to chlorinating agent in step (3) is 1.0: 1.0-1.6; the temperature of the chlorination reaction is 30-100 ℃, and the reaction time is 3-8 h.
7. The method according to claim 1 or 6, wherein said chlorinating agent is phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosphorus pentachloride or phosphorus trichloride; the solvent is tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide, N-diethylformamide, 1, 4-dioxane or acetonitrile.
8. The method according to claim 1, wherein the molar ratio of the 4-chloro-6, 7-difluoroquinazoline, the 3-ethynylaniline, and the base reagent in step (4) is 1.0: 1.3 to 1.8: 1.8 to 2.5; the condensation reaction is carried out at the temperature of 50-100 ℃ for 6-12 h; the alkali reagent is sodium hydroxide, potassium carbonate, sodium carbonate or cesium carbonate; the solvent is dichloromethane, 1, 2-dichloroethane, chloroform, toluene, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, methyl tert-butyl ether, acetonitrile or 1, 4-dioxane.
9. The method according to claim 1, wherein the molar ratio of 4- [ (3-ethynylphenyl) amino ] -6, 7-difluoroquinazoline and triethylene glycol to the base reagent in step (5) is 1.0: 1.0-1.3: 1.3-1.8; the temperature of the etherification reaction is 60-100 ℃, and the reaction time is 4-24 h; the solvent is dichloromethane, 1, 2-dichloroethane, chloroform, toluene, N-dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether, 1, 4-dioxane, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran.
10. The method of claim 1 or 9, wherein the base reagent is sodium metal, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium isopropoxide, potassium isopropoxide, or potassium tert-pentoxide.
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* Cited by examiner, † Cited by third party
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CN1534026A (en) * 2002-03-28 2004-10-06 �Ϳ���ҽҩ��˾ Condensed quinazoline derirative used as tyrosine kinase inhibitor
CN105017208A (en) * 2014-04-28 2015-11-04 宁波文达医药科技有限公司 Improved icotinib and method for preparing intermediate thereof
CN107200715A (en) * 2017-06-22 2017-09-26 陕西师范大学 Quinazoline derivant and its application in antineoplastic is prepared

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NZ590334A (en) * 2008-07-08 2012-12-21 Beta Pharma Inc ICOTINIB HYDROCHLORIDE (4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crownquinazoline hydrochloride), SYNTHESIS, CRYSTALLOGRAPHIC FORM, MEDICAL COMBINATION, AND USES THEREOF
AU2012331547C1 (en) * 2011-10-31 2016-04-21 Betta Pharmaceuticals Co., Ltd Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof
CN111763214B (en) * 2020-08-10 2022-03-15 苏州富士莱医药股份有限公司 Preparation method of icotinib

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1534026A (en) * 2002-03-28 2004-10-06 �Ϳ���ҽҩ��˾ Condensed quinazoline derirative used as tyrosine kinase inhibitor
CN105017208A (en) * 2014-04-28 2015-11-04 宁波文达医药科技有限公司 Improved icotinib and method for preparing intermediate thereof
CN107200715A (en) * 2017-06-22 2017-09-26 陕西师范大学 Quinazoline derivant and its application in antineoplastic is prepared

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