CN111362957B - Preparation method of icotinib key intermediate - Google Patents
Preparation method of icotinib key intermediate Download PDFInfo
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Abstract
The invention discloses a preparation method of an icotinib key intermediate, belonging to the technical field of drug synthesis. The technical scheme provided by the invention has the key points that: the invention respectively uses triethylene-bis (p-toluenesulfonate) and N-Boc-3, 4-dihydroxyaniline as raw materials, and respectively carries out crown ether cyclization reaction, halogenation reaction and ammoniation reaction (amidation reaction), quinoline cyclization reaction is carried out, and finally chlorination reaction is carried out to obtain a key intermediate 4-chloro-quinazolino [6.7-6] -12-crown-4 of icotinib; the newly designed synthetic route avoids the need of using a strong acid solution in the original route, avoids the operation danger and generates a large amount of acidic waste liquid, and is simple to operate and high in reaction yield.
Description
Technical Field
The invention belongs to the technical field of synthesis of medicaments, and particularly relates to a preparation method of an icotinib key intermediate.
Background
The erlotinib (Camina, hydrochloric acid) is an anti-tumor 1.1 new drug which is completely independently developed by Chinese scientists and tumor clinical experts based on erlotinib by Berda pharmaceutical industry GmbH, is approved by the national food and drug administration to be marketed in 2011 in 6 months, and is used for treating NSCLC patients with EGFR mutation. The great significance of the Icotinib is that the Icotinib and the gefitinib have good safety and obvious advantages in toxic and side reactions, the incidence rate of rash and diarrhea is low, more patients are benefited, more importantly, the monopoly of foreign drug enterprises on the small molecule targeted drug market is broken, the EGFR inhibitor which is cheap and high in quality and safety is provided in China, the economic pressure of the patients is greatly reduced, and more hopes are brought to the advanced NSCLC patients in China.
The 4-chloro-quinazolino [6.7-6] -12-crown-4 is a key intermediate for preparing the icotinib, the production cost is high, the quality of the product directly affects the icotinib, the existing preparation method of the 4-chloro-quinazolino [6.7-6] -12-crown-4 is very limited, 3, 4-dihydroxy ethyl benzoate is mainly used as a starting material and is obtained through the routes of cyclization, digestion, reduction, cyclization and the like, a strong acid solution is required to be used in the method, the operation is dangerous, a large amount of acidic waste liquid is generated, and the environment is greatly damaged, so that the discovery of a new preparation method of the 4-chloro-quinazolino [6.7-6] -12-crown-4 has very important significance. By carrying out communication and cooperation with the southern Kai university and the Jinan Aisi medicine science and technology limited company, a brand new synthetic route is developed, and many defects of the existing process can be overcome.
Disclosure of Invention
The preparation method of the icotinib key intermediate is characterized by comprising the following two methods:
(1) performing crown ether cyclization, chlorination reaction, amino substitution and quinoline cyclization on 3, 4-dihydroxy ethyl benzoate to obtain 4-carbonyl-quinazolino [6.7-6] -12-crown-4;
the crown ether cyclization in the step (1) is as follows: in a supercritical reaction kettle, a certain amount of triethylene-bis (p-toluenesulfonate) and 3, 4-dihydroxy ethyl benzoate are placed in the reaction kettle, then the whole system is vacuumized and stirred, ammonia gas is introduced into the reaction kettle to ensure that the pressure in the reaction kettle reaches normal pressure, then introducing carbon dioxide, gradually making the carbon dioxide become liquid, fully dissolving triethylenebis (p-toluenesulfonate) and ethyl 3, 4-dihydroxybenzoate, raising the temperature in the reaction kettle to a certain temperature, stopping the reaction after reacting for a certain time, slowly releasing the carbon dioxide, enabling the reaction kettle to present turbid solid, then adding a certain amount of mixed solution of methanol and acetone into the turbid solid, stirring for a period of time at 0 ℃, filtering and drying to obtain 3,4- (benzo-12-crown-4) ethyl benzoate; the feeding amount molar ratio of the triethylenebis (p-toluenesulfonate) to the ethyl 3, 4-dihydroxybenzoate is 1: 1-1.1; the reaction temperature is 30-50 ℃.
The chlorination reaction in the step (1) is as follows: dissolving a certain amount of 3,4- (benzo-12-crown-4) ethyl benzoate in dichloroethane, stirring for a period of time at 40 ℃, then adding N-chlorosuccinimide in batches, slowly heating to a certain temperature after adding, cooling to room temperature after reacting for a period of time, filtering reaction liquid, pouring filtrate into ice water, adding saturated sodium hydroxide solution, separating out an organic phase, adjusting the pH of the organic phase to be neutral by using dilute hydrochloric acid solution, separating out the organic phase again, drying by using anhydrous magnesium sulfate, and concentrating to obtain 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate; the feeding amount molar ratio of the ethyl 3,4- (benzo-12-crown-4) benzoate to the ethyl 3,4- (benzo-12-crown-4) benzoate is 1: 1-1.1; the reaction temperature is 55-65 DEG C
The amino substitution in the step (1) is as follows: adding a certain amount of 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate, tris (triphenylphosphine) cobalt chloride, DBU and cesium carbonate into anhydrous toluene, stirring uniformly, replacing gas for many times by nitrogen gas in a reaction bottle, slowly heating to reflux, cooling to room temperature, slowly dropwise adding a toluene solution dissolved with azidotrimethylsilane and potassium iodide, heating to 50 ℃ after dropwise adding, keeping the temperature for reaction for a period of time, cooling to reflux, adding an aqueous solution dissolved with ammonium sulfamate into a water separator, refluxing the toluene, entering a water separator, mixing with water, slowly dropwise adding a mixed solution into the reaction solution through the water separator, continuously circulating through a reflux system, continuously reacting for a period of time, cooling to room temperature, then dropwise adding dilute hydrochloric acid into the filtrate to enable the pH of the filtrate to reach 1-2, slowly stirring at 10 deg.C to gradually precipitate solid, filtering, collecting filter cake, and drying to obtain 6-amino-3, 4- (benzo-12-crown-4) ethyl benzoate hydrochloride; the mass ratio of the 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate to the tri (triphenylphosphine) cobalt chloride to the DBU is 10: 0.1-0.2: 0.3; the feeding amount molar ratio of the 6-nitro-3, 4- (benzo-12-crown-4) ethyl benzoate to the cesium carbonate is 2: 1; the feeding amount molar ratio of the 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate to the azidotrimethylsilane to the potassium iodide is 1: 1-1.2; the molar ratio of the 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate to the ammonium sulfamate is 1:1.
The quinoline cyclization reaction in the step (1) is as follows: adding a certain amount of 6-amino-3, 4- (benzo-12-crown-4) ethyl benzoate hydrochloride into formamide in a reaction bottle, then adding ammonium formate, slowly heating to a certain temperature in a nitrogen atmosphere, reacting until the raw materials completely react, cooling to room temperature, adding ethyl acetate and water into the reaction solution, separating out an organic phase, and concentrating to obtain 4-carbonyl-quinazolino [6.7-6] -12-crown-4; the feeding amount molar ratio of the 6-amino-3, 4- (benzo-12-crown-4) ethyl benzoate hydrochloride to the ammonium formate is 1: 3; the temperature is 120-170 ℃.
(2) Performing crown ether cyclization, chlorination, formamide substitution and quinoline cyclization on N-Boc-3, 4-dihydroxyaniline to obtain 4-carbonyl-quinazolino [6.7-6] -12-crown-4;
the crown ether cyclization reaction in the step (2) is as follows: adding a certain amount of N-Boc-3, 4-dihydroxyaniline and anhydrous barium hydroxide into N, N-dimethylformamide, heating to a certain temperature under the protection of nitrogen, stirring for a period of time, then slowly adding an N, N-dimethylformamide solution dissolved with triethylenetetramine (p-toluenesulfonate), continuing the reaction at the temperature until the raw materials are completely reacted, evaporating N, N-dimethylformamide in vacuum, adding the concentrate into dichloromethane, adding trifluoroacetic acid and concentrated sulfuric acid, stirring for a period of time at the temperature of 0-10 ℃, adding water, filtering, separating out an organic phase, extracting the reaction liquid with dichloromethane for multiple times in a water phase, combining the organic phases, adjusting the pH value to be neutral with saturated sodium hydroxide, separating out the organic phase, and concentrating to obtain 3,4- (benzo-12-crown-4) aniline; the feeding amount molar ratio of the N-Boc-3, 4-dihydroxyaniline to anhydrous barium hydroxide is 1: 1-1.2; the reaction temperature is 70-100 ℃.
The chlorination reaction in the step (2) is as follows: dissolving a certain amount of 3,4- (benzo-12-crown-4) aniline in dichloroethane, stirring for dissolving, adding N-chlorosuccinimide, slowly heating to 70 ℃, reacting for a period of time, monitoring the reaction completion of raw materials by TLC, cooling to room temperature, filtering the reaction solution, pouring the filtrate into ice water, adding saturated sodium hydroxide solution, separating out an organic phase, adjusting the pH of the organic phase to be neutral by using dilute hydrochloric acid solution, separating out the organic phase again, drying by using anhydrous magnesium sulfate, and concentrating to obtain 6-chloro-3, 4- (benzo-12-crown-4) aniline; the charged molar ratio of the 3,4- (benzo-12-crown-4) aniline to the N-chlorosuccinimide is 1: 1.5.
The formamide substitution in the step (2) is as follows: adding a certain amount of 6-amino-3, 4- (benzo-12-crown-4) phenyl chloride, nickel chloride, 1' -bis (diphenylphosphino) ferrocene, zinc powder and N, N-dimethylformamide into a closed reaction bottle, heating to a certain temperature under the protection of oxygen, stirring for reacting for a period of time, slowly dropwise adding a certain amount of N, N-dimethylformamide solution in which polycarbodiimide is dissolved, keeping the oxygen atmosphere, raising the temperature after dropwise adding, stirring for reacting for a period of time at room temperature, adding water into the reaction solution after the reaction is finished, adjusting the pH of the reaction solution to 7-8 by using dilute hydrochloric acid, filtering the reaction solution, extracting for multiple times by using dichloromethane, combining organic phases, washing the organic phase for multiple times by using a saturated sodium carbonate solution, concentrating the organic phase, finally, purifying the residue by column chromatography to obtain 6-amino-3, 4- (benzo-12-crown-4) benzamide; the feeding amount molar ratio of the 6-amino-3, 4- (benzo-12-crown-4) phenyl chloride to the nickel chloride to the 1,1' -bis (diphenylphosphino) ferrocene to the zinc powder is 1:0.5:0.1: 1-2; the feeding amount molar ratio of the 6-amino-3, 4- (benzo-12-crown-4) phenyl chloride to the polycarbodiimide is 1: 3-5; the reaction temperature is 50-70 ℃.
The quinoline cyclization reaction in the step (2) is as follows: adding a certain amount of 6-amino-3, 4- (benzo-12-crown-4) benzamide into triethyl orthoformate, heating until the refluxing raw materials react completely, cooling to room temperature, filtering to obtain a crude product, and washing a filter cake with methyl tert-butyl ether to obtain the 4-carbonyl-quinazolino [6.7-6] -12-crown-4.
(3) Adding a certain amount of 4-carbonyl-quinazolino [6.7-6] -12-crown-4 and N, N-dimethylformamide into dichlorosulfoxide, stirring uniformly, slowly heating up and refluxing, after the reaction is finished, taking out thionyl chloride by using toluene, washing the obtained solid by using toluene, and drying to obtain 4-chloro-quinazolino [6.7-6] -12-crown-4.
The invention has the technical advantages that: the newly designed synthetic route avoids the need of using a strong acid solution in the original route, avoids the operation danger and generates a large amount of acidic waste liquid, and is simple to operate and high in reaction yield.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
Putting 50g of triethylenedi (p-toluenesulfonate) and 20g of ethyl 3, 4-dihydroxybenzoate in a supercritical reaction kettle, vacuumizing the whole system, stirring, introducing ammonia gas into the reaction kettle to ensure that the pressure in the reaction kettle reaches normal pressure, introducing carbon dioxide, increasing the pressure in the reaction kettle to 12MPa, gradually making the carbon dioxide into a liquid state, fully dissolving the triethylenedi (p-toluenesulfonate) and the ethyl 3, 4-dihydroxybenzoate, raising the temperature in the reaction kettle to 50 ℃, stopping the reaction after reacting for a certain time, slowly discharging the carbon dioxide, enabling the reaction kettle to present a turbid solid, adding a mixed solution of 70mL of methanol and 30mL of acetone, stirring for 10min at the temperature of 0 ℃, filtering, drying to obtain 27.2g of the ethyl 3,4- (benzo-12-crown-4) benzoate, the ester hydrolysis by-products and dimer by-products can be effectively avoided, and the reaction yield is improved;1H NMR(400Hz,DMSO-d6):7.62(t,J1＝4.0Hz,J2＝4.0Hz,1H), 7.56(s,1H),7.14(d,J＝4.0Hz,1H),4.28(dd,J1＝4.0Hz,J2＝4.0Hz,2H),4.18-4.14(m,4H), 3.75-3.67(m,4H),3.61(s,4H),1.30(t,J1＝8.0Hz,J2＝4.0Hz,3H)。
example 2
Dissolving 30g of ethyl 3,4- (benzo-12-crown-4) benzoate in 300mL of dichloroethane, stirring for 20min at 40 ℃, then adding 15g of N-chlorosuccinimide in three batches with a time interval of 1h of 5g for each batch, slowly heating to 55 ℃ after the last batch of NCS is added, reacting for a period of time, monitoring the complete reaction of raw materials by TLC, cooling to room temperature, filtering the reaction solution, pouring the filtrate into 1000mL of ice water, adding 200mL of saturated sodium hydroxide solution, separating out an organic phase, adjusting the pH of the organic phase to be neutral by using a dilute hydrochloric acid solution, separating out the organic phase again, drying by using anhydrous magnesium sulfate, concentrating to obtain 30g of ethyl 6-chloro-3, 4- (benzo-12-crown-4) benzoate,1H NMR(400Hz,DMSO-d6):7.34(s,1H),6.95(s,1H),4.26(dd, J1＝8.0Hz,J2＝4.0Hz,2H),4.01(t,J1＝4.0Hz,J2＝4.0Hz,2H),3.98-3.96(m,2H),3.81(t,J1＝4.0Hz, J2＝4.0Hz,2H),3.69-3.66(m,2H),3.61(s,4H),1.28(t,J1＝4.0Hz,J2＝4.0Hz,3H)；LC-MS(ESI)： 331[M+H]+。
example 3
Dissolving 30g of ethyl 3,4- (benzo-12-crown-4) benzoate in 300mL of dichloroethane, stirring for 20min at 40 ℃, then adding 15g of N-chlorosuccinimide in one step, slowly heating to 60 ℃, after reacting for a period of time, monitoring the complete reaction of raw materials by TLC, cooling to room temperature, filtering the reaction liquid, pouring the filtrate into 1000mL of ice water, adding 200mL of saturated sodium hydroxide solution, separating out an organic phase, adjusting the pH of the organic phase to be neutral by using dilute hydrochloric acid solution, and separating out the organic phase againThe organic phase was dried over anhydrous magnesium sulfate and concentrated to give 22g of ethyl 6-chloro-3, 4- (benzo-12-crown-4) benzoate,1H NMR(400Hz, DMSO-d6):7.34(s,1H),6.95(s,1H),4.26(dd,J1＝8.0Hz,J2＝4.0Hz,2H),4.01(t,J1＝4.0Hz, J2＝4.0Hz,2H),3.98-3.96(m,2H),3.81(t,J1＝4.0Hz,J2＝4.0Hz,2H),3.69-3.66(m,2H),3.61(s, 4H),1.28(t,J1＝4.0Hz,J2＝4.0Hz,3H)；LC-MS(ESI)：331[M+H]+。
example 4
Adding 30g of 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate, 3.5g of tris (triphenylphosphine) cobalt chloride, 3.5g of DBU10g and 16g of cesium carbonate into 400mL of anhydrous toluene in a closed reaction bottle with a water separator, uniformly stirring, replacing gas for three times by nitrogen in the reaction bottle, slowly heating to reflux, carrying out reflux stirring reaction for 40min, cooling to room temperature, slowly dropwise adding 100mL of toluene solution in which 14g of trimethylsilyl azide and 1.7g of potassium iodide are dissolved, heating to 50 ℃ after dropwise adding, keeping the temperature for reaction for 4h, heating to reflux, adding 30mL of aqueous solution in which 12g of ammonium sulfamate is dissolved into the water separator, refluxing the toluene, mixing the toluene with the aqueous solution in the water separator, slowly dropwise adding the mixed solution into the reaction solution through the water separator, paying attention to heat release in the initial stage, the stirring and the temperature are controlled to prevent a large amount of waterfall boiling, after the control is stable, the continuous circulation is carried out through a reflux system, the reaction is continuously carried out for 2 hours, the reaction is reduced to the room temperature, then dilute hydrochloric acid is dropwise added into the filtrate, the pH value of the filtrate is enabled to reach 1-2, the slow stirring is carried out at the temperature of 10 ℃, solids are gradually separated out, the recrystallization is carried out in petroleum ether after the filtration, then the filtration is carried out again, the filter cake is collected and dried, and 31g of 6-amino-3, 4- (benzo-12-crown-4) ethyl benzoate hydrochloride is obtained;1H NMR(400Hz,DMSO-d6):7.31(s,1H),6.49(s,2H),6.32(s,1H),4.20(dd,J1＝8.0Hz,J2＝4.0Hz, 2H),4.01(t,J1＝4.0Hz,J2＝4.0Hz,2H),3.95-3.94(m,2H),3.79(t,J1＝4.0Hz,J2＝4.0Hz,2H), 3.64-3.60(m,6H),1.28(t,J1＝4.0Hz,J2＝4.0Hz,3H)；13C NMR(400Hz,DMSO-d6):167.25, 157.19,150.04,139.63,122.06,101.49,101.35,74.71,71.56,70.23,69.65,69.15,68.82,59.97, 14.77。
example 5
Adding 30g of 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate, 7.0g of tris (triphenylphosphine) cobalt chloride, 10g of DBU10g and 16g of cesium carbonate into 300mL of anhydrous toluene in a closed reaction bottle with a water separator, uniformly stirring, replacing gas for three times in the reaction bottle by nitrogen, slowly heating to reflux, carrying out reflux stirring reaction for 20min, cooling to room temperature, slowly dropwise adding 100mL of toluene solution in which 14g of trimethylsilyl azide and 1.7g of potassium iodide are dissolved, heating to 50 ℃ after dropwise adding, keeping the temperature for reaction for 3h, heating to reflux, adding 30mL of aqueous solution in which 12g of ammonium sulfamate is dissolved into the water separator, refluxing the toluene, mixing the toluene with the aqueous solution in the water separator, slowly dropwise adding mixed solution into the reaction solution through the water separator, paying attention to heat release of the reaction solution at the initial stage, the stirring and the temperature are controlled to prevent a large amount of waterfall boiling, the reaction is continuously carried out for 1.5h through a reflux system after the control is stable, the reaction is cooled to the room temperature, then dilute hydrochloric acid is dropwise added into the filtrate, the pH value of the filtrate reaches 1-2, the filtrate is slowly stirred at the temperature of 10 ℃, solids are gradually separated out, the filtrate is recrystallized in petroleum ether after the filtration, then the filtrate is filtered again, a filter cake is collected and dried, and 26.5g of 6-amino-3, 4- (benzo-12-crown-4) ethyl benzoate hydrochloride is obtained;1H NMR(400Hz,DMSO-d6):7.31(s,1H),6.49(s,2H),6.32(s,1H),4.20(dd,J1＝8.0Hz, J2＝4.0Hz,2H),4.01(t,J1＝4.0Hz,J2＝4.0Hz,2H),3.95-3.94(m,2H),3.79(t,J1＝4.0Hz,J2＝4.0Hz, 2H),3.64-3.60(m,6H),1.28(t,J1＝4.0Hz,J2＝4.0Hz,3H)；13C NMR(400Hz,DMSO-d6):167.25, 157.19,150.04,139.63,122.06,101.49,101.35,74.71,71.56,70.23,69.65,69.15,68.82,59.97, 14.77。
example 6
Adding 35g of 6-amino-3, 4- (benzo-12-crown-4) ethyl benzoate hydrochloride into 290mL of formamide in a reaction bottle, adding 20g of ammonium formate, slowly heating to 165 ℃ in a nitrogen atmosphere, reacting for 7h, monitoring the completion of the reaction of raw materials by TLC, cooling to room temperature, adding 200mL of ethyl acetate and 100mL of water into the reaction solution, separating an organic phase, and concentrating to obtain 4-carbonyl-quinazolino [6.7-6]]-12-crown-4 (24.4 g);1H NMR(400Hz,DMSO-d6):12.07(s,1H), 7.99(s,1H),7.61(s,1H),7.23(s,1H),4.26-4.19(m,4H),3.78-3.69(m,4H),3.62(s,4H)；13C NMR(400Hz,DMSO-d6):160.45,156.86,150.04,146.30,144.79,117.11,113.77,112.10, 73.22,71.02,70.94,70.53,69.24,68.94。
example 7
Adding 22.5g of N-Boc-3, 4-dihydroxyaniline and 17g of anhydrous barium hydroxide into 150mL of N, N-dimethylformamide in a reaction bottle, heating to 90 ℃ under the protection of nitrogen, stirring for 30min, slowly adding 150mL of N, N-dimethylformamide solution dissolved with 50g of triethylenetetramine-bis (p-toluenesulfonate), continuing to react for 5h at 90 ℃, monitoring the reaction completion of raw materials by TLC, evaporating 220mL of N, N-dimethylformamide in vacuum, adding 100mL of dichloromethane into the concentrate, adding 5mL of trifluoroacetic acid and 2mL of concentrated sulfuric acid, stirring for 3h at 0-10 ℃, releasing heat when adding mixed acid, controlling temperature and stirring, adding 50mL of water, filtering, separating out an organic phase, extracting the aqueous phase with 50mL of dichloromethane for 4 times, mixing organic phases, adjusting pH to neutral with saturated sodium hydroxide, separating organic phase, concentrating, and separating by silica gel column chromatography17g of 3,4- (benzo-12-crown-4) aniline; LC-MS (ESI): 240[ M + H ]]+。
Example 8
Adding 22.5g of N-Boc-3, 4-dihydroxyaniline and 20g of anhydrous barium hydroxide into 150mL of N, N-dimethylformamide in a reaction bottle, heating to 90 ℃ under the protection of nitrogen, stirring for 30min, slowly adding 150mL of N, N-dimethylformamide solution dissolved with 50g of triethylenetetramine-bis (p-toluenesulfonate), continuing to react for 4h at 90 ℃, monitoring the reaction completion of raw materials by TLC, evaporating 220mL of N, N-dimethylformamide in vacuum, adding 100mL of dichloromethane into the concentrate, adding 5mL of trifluoroacetic acid and 3mL of concentrated sulfuric acid, stirring for 3h at 0-10 ℃, releasing heat when adding mixed acid, controlling temperature and stirring, adding 50mL of water, filtering, separating out an organic phase, extracting the aqueous phase with 50mL of dichloromethane for 4 times, mixing organic phases, adjusting pH to neutral with saturated sodium hydroxide, separating organic phase, and concentrating to obtain 22.4g of 3,4- (benzo-12-crown-4) aniline; LC-MS (ESI): 240[ M + H ]]+。
Example 9
Dissolving 24g of 3,4- (benzo-12-crown-4) aniline in 300mL of dichloroethane, stirring for dissolving, adding 20g of N-chlorosuccinimide in batches, keeping the time interval of 5g of each batch for 1h, slowly heating to 70 ℃ after the last batch of NCS is added, reacting for a period of time, monitoring the complete reaction of raw materials by TLC, cooling to room temperature, filtering the reaction solution, pouring the filtrate into 1000mL of ice water, adding 200mL of saturated sodium hydroxide solution, separating out an organic phase, adjusting the pH of the organic phase to be neutral by using dilute hydrochloric acid solution, separating out the organic phase again, drying by using anhydrous magnesium sulfate, concentrating to obtain 24.7g of 6-chloro-3, 4- (benzo-12-crown-4) aniline,1H NMR(400Hz,DMSO-d6):7.08(s,1H),6.85(s,1H),6.24(s,2H),4.07-4.03(m,4H),3.91(dd, J1＝8.0Hz,J2＝4.0Hz,2H),3.85(t,J1＝4.0Hz,J2＝4.0Hz,2H),3.59-3.56(m,2H),3.51(t,J1＝4.0Hz, J2＝8.0Hz,2H)；LC-MS(ESI)：274[M+H]+。
example 10
Adding 27g of 6-amino-3, 4- (benzo-12-crown-4) phenyl chloride, 6.5g of nickel chloride, 3.2g of 1,1' -bis (diphenylphosphino) ferrocene, 13g of zinc powder and 300mL of N, N-dimethylformamide into a closed reaction bottle, heating to 50 ℃ under the protection of oxygen, stirring for reaction for 2 hours, then placing at-5 ℃, slowly dropwise adding 150mL of N, N-dimethylformamide solution dissolved with 13g of polycarbodiimide, keeping the oxygen atmosphere, raising the temperature after dropwise adding, stirring for reaction at room temperature for 6 hours, after the reaction is finished, adding 300mL of water into the reaction solution, then adjusting the pH of the reaction solution to 7-8 with dilute hydrochloric acid, filtering the reaction solution, collecting filter cakes, using the filter cakes again, extracting with dichloromethane for multiple times, combining organic phases, washing the organic phases with a saturated sodium carbonate solution for multiple times, then the organic phase is concentrated, and the final residue is purified by recrystallization from petroleum ether to give 23.7g of 6-amino-3, 4- (benzo-12-crown-4) benzamide, calculated value for elemental analysis [ C ]13H18N2O5]C, 55.31; h, 6.43; n,9.92, found C, 55.43; h, 6.47; and N, 9.89.
Example 11
Adding 27g of 6-amino-3, 4- (benzo-12-crown-4) phenyl chloride, 6.5g of nickel chloride, 5.5g of 1,1' -bis (diphenylphosphino) ferrocene, 6.5g of zinc powder and 300mL of N, N-dimethylformamide into a closed reaction bottle, heating to 50 ℃ under the protection of oxygen, stirring for reaction for 2 hours, then placing at-5 ℃, slowly dropwise adding 150mL of N, N-dimethylformamide solution dissolved with 13g of polycarbodiimide, and keeping the oxygen atmosphereAfter the dropwise addition, the reaction solution is stirred at room temperature for 6 hours, 300mL of water is added into the reaction solution after the reaction is finished, then diluted hydrochloric acid is used for adjusting the pH value of the reaction solution to 7-8, the reaction solution is filtered, dichloromethane is used for extraction for multiple times, organic phases are combined, the organic phase is washed for multiple times by saturated sodium carbonate solution, then the organic phase is concentrated, and finally the rest is purified by column chromatography to obtain 17.5g of 6-amino-3, 4- (benzo-12-crown-4) benzamide; calculated value of elemental analysis [ C13H18N2O5]C, 55.31; h, 6.43; n,9.92, found C, 55.43; h, 6.47; and N, 9.89.
Example 12
Adding 27g of 6-amino-3, 4- (benzo-12-crown-4) phenyl chloride, 6.5g of nickel chloride, 3.2g of 1,1' -bis (diphenylphosphino) ferrocene, 13g of zinc powder and 300mL of N, N-dimethylformamide into a closed reaction bottle, heating to 50 ℃ under the protection of oxygen, stirring for reaction for 2 hours, then placing at-5 ℃, slowly dropwise adding 200mL of N, N-dimethylformamide solution dissolved with 21g of polycarbodiimide, keeping the oxygen atmosphere, raising the temperature after dropwise adding, stirring for reaction at room temperature for 4 hours, after the reaction is finished, adding 350mL of water into the reaction solution, then adjusting the pH of the reaction solution to 7-8 with dilute hydrochloric acid, filtering the reaction solution, then extracting with dichloromethane for multiple times, combining organic phases, washing the organic phase with a saturated sodium carbonate solution for multiple times, then concentrating the organic phase, and finally recrystallizing and purifying the residue by petroleum ether to obtain 26.1g of 6-amino-3, 4- (benzo-12-crown-4) benzamide; elemental analysis calculated value [ C13H18N2O5]C, 55.31; h, 6.43; n,9.92, found C, 55.43; h, 6.47; and N, 9.89.
Example 13
28g of 6-amino-3, 4- (benzo-12-crown-4) benzamide was added to 250g of triethyl orthoformate, and the mixture was heated to refluxFlowing for 1h, monitoring the reaction of the raw materials by TLC, cooling to room temperature, filtering to obtain a crude product, and washing a filter cake with methyl tert-butyl ether to obtain 4-carbonyl-quinazolino [ 6.7-6%]-12-crown-4 (25.7 g);1H NMR(400Hz,DMSO-d6):12.07(s,1H),7.99 (s,1H),7.61(s,1H),7.23(s,1H),4.26-4.19(m,4H),3.78-3.69(m,4H),3.62(s,4H)；13C NMR (400Hz,DMSO-d6):160.45,156.86,150.04,146.30,144.79,117.11,113.77,112.10,73.22, 71.02,70.94,70.53,69.24,68.94。
example 14
In a reaction flask, 4-carbonyl-quinazolino [6.7-6]]Adding-12-crown-4 (29g) and 2.9g of N, N-dimethylformamide into 150mL of thionyl chloride, stirring uniformly, slowly heating to reflux, reacting for 3 hours, concentrating in vacuum, adding 100mL of toluene, concentrating in vacuum again, taking out unreacted dichloromethane three times by using toluene, adding 100mL of toluene for the last time, performing suction filtration, drying a filter cake to obtain 4-chloro-quinazolino [6.7-6]]-12-crown-4 (27.1 g);1H NMR(400Hz, DMSO-d6):8.91(s,1H),7.68(s,1H),7.59(s,1H),4.39-4.35(m,4H),3.81(d,J＝4.0Hz,2H), 3.74(t,J1＝4.0Hz,J2＝4.0Hz,2H),3.62(s,4H)；13C NMR(400Hz,DMSO-d6):159.08,153.12, 149.46,119.47,111.69,111.31,73.77,71.51,70.90,70.52,69.11,68.66。
while the foregoing embodiments have described the general principles, principal features and advantages of the invention, it will be understood by those skilled in the art that the invention is not limited thereto, and that the foregoing embodiments and descriptions are provided only for the purpose of illustrating the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the invention.
Claims (8)
1. A preparation method of an icotinib key intermediate is characterized in that the preparation method of the icotinib key intermediate comprises the following specific steps:
(1) performing crown ether cyclization, chlorination reaction, amino substitution and quinoline cyclization on 3, 4-dihydroxy ethyl benzoate to obtain 4-carbonyl-quinazolino [6.7-6] -12-crown-4; or
(1') carrying out crown ether cyclization, chlorination reaction, formamide substitution and quinoline cyclization on N-Boc-3, 4-dihydroxyaniline to obtain 4-carbonyl-quinazolino [6.7-6] -12-crown-4;
(2) 4-carbonyl-quinazolino [6.7-6] -12-crown-4 reacts with thionyl chloride to obtain 4-chloro-quinazolino [6.7-6] -12-crown-4;
the amino substitution in the step (1) is as follows: adding a certain amount of 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate, tris (triphenylphosphine) cobalt chloride, DBU and cesium carbonate into anhydrous toluene, stirring uniformly, replacing gas for many times by nitrogen gas in a reaction bottle, slowly heating to reflux, cooling to room temperature, slowly dropwise adding a toluene solution dissolved with azidotrimethylsilane and potassium iodide, heating to 50 ℃ after dropwise adding, keeping the temperature for reaction for a period of time, cooling to reflux, adding an aqueous solution dissolved with ammonium sulfamate into a water separator, refluxing the toluene, entering the water separator into the water separator to mix with water, slowly dropwise adding a mixed solution into a reaction solution through the water separator, continuously circulating through a reflux system, continuously reacting for a period of time, cooling to room temperature, dropwise adding dilute hydrochloric acid into a filtrate to enable the pH value of the filtrate to reach 1-2, slowly stirring at 10 ℃, gradually precipitating solids, filtering, collecting a filter cake, and drying to obtain 6-amino-3, 4- (benzo-12-crown-4) ethyl benzoate hydrochloride; the mass ratio of the 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate to the tris (triphenylphosphine) cobalt chloride to the DBU is 10: 0.1-0.2: 0.3; the feeding amount molar ratio of the 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate to the cesium carbonate is 2: 1; the feeding amount molar ratio of the 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate to the azidotrimethylsilane to the potassium iodide is 1: 1-1.2; the feeding amount molar ratio of the 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate to the ammonium sulfamate is 1: 1;
the formamide substitution in the step (1') is as follows: adding a certain amount of 6-amino-3, 4- (benzo-12-crown-4) phenyl chloride, nickel chloride, 1' -bis (diphenylphosphino) ferrocene, zinc powder and N, N-dimethylformamide into a closed reaction bottle, heating to a certain temperature under the protection of oxygen, stirring for reacting for a period of time, slowly dropwise adding a certain amount of N, N-dimethylformamide solution in which polycarbodiimide is dissolved, keeping the oxygen atmosphere, heating to room temperature after dropwise adding, stirring for reacting for a period of time, adding water into the reaction solution after the reaction is finished, adjusting the pH of the reaction solution to 7-8 by using dilute hydrochloric acid, filtering the reaction solution, extracting for multiple times by using dichloromethane, combining organic phases, washing the organic phase for multiple times by using a saturated sodium carbonate solution, concentrating the organic phase, finally, purifying the residue by column chromatography to obtain 6-amino-3, 4- (benzo-12-crown-4) benzamide; the feeding amount molar ratio of the 6-amino-3, 4- (benzo-12-crown-4) phenyl chloride to the nickel chloride to the 1,1' -bis (diphenylphosphino) ferrocene to the zinc powder is 1:0.5:0.1: 1-2; the feeding amount molar ratio of the 6-amino-3, 4- (benzo-12-crown-4) phenyl chloride to the polycarbodiimide is 1: 3-5; the certain temperature is 50-70 ℃.
2. The process for the preparation of icotinib key intermediate according to claim 1, characterized in that: the crown ether cyclization in the step (1) is as follows: in a supercritical reaction kettle, a certain amount of triethylene-bis (p-toluenesulfonate) and 3, 4-dihydroxy ethyl benzoate are placed in the reaction kettle, then the whole system is vacuumized and stirred, ammonia gas is introduced into the reaction kettle to ensure that the pressure in the reaction kettle reaches normal pressure, then introducing carbon dioxide, gradually changing the carbon dioxide into liquid state, fully dissolving triethylenebis (p-toluenesulfonate) and ethyl 3, 4-dihydroxybenzoate, raising the temperature in the reaction kettle to a certain temperature, stopping the reaction after reacting for a certain time, slowly releasing the carbon dioxide, enabling the reaction kettle to present turbid solid, then adding a certain amount of mixed solution of methanol and acetone into the turbid solid, stirring for a period of time at 0 ℃, filtering and drying to obtain 3,4- (benzo-12-crown-4) ethyl benzoate; the feeding amount molar ratio of the triethylenebis (p-toluenesulfonate) to the ethyl 3, 4-dihydroxybenzoate is 1: 1-1.1; the certain temperature is 30-50 ℃.
3. The process for the preparation of icotinib key intermediate according to claim 1, characterized in that: the chlorination reaction in the step (1) is as follows: dissolving a certain amount of 3,4- (benzo-12-crown-4) ethyl benzoate in dichloroethane, stirring for a period of time at 40 ℃, then adding N-chlorosuccinimide in batches, slowly heating to a certain temperature after adding, cooling to room temperature after reacting for a period of time, filtering reaction liquid, pouring filtrate into ice water, adding saturated sodium hydroxide solution, separating out an organic phase, adjusting the pH of the organic phase to be neutral by using dilute hydrochloric acid solution, separating out the organic phase again, drying by using anhydrous magnesium sulfate, and concentrating to obtain 6-chloro-3, 4- (benzo-12-crown-4) ethyl benzoate; the feeding amount molar ratio of the ethyl 3,4- (benzo-12-crown-4) benzoate to the ethyl 3,4- (benzo-12-crown-4) benzoate is 1: 1-1.1; the certain temperature is 55-65 ℃.
4. The process for the preparation of icotinib key intermediate according to claim 1, characterized in that: the quinoline cyclization reaction in the step (1) is as follows: adding a certain amount of 6-amino-3, 4- (benzo-12-crown-4) ethyl benzoate hydrochloride into formamide in a reaction bottle, then adding ammonium formate, slowly heating to a certain temperature in a nitrogen atmosphere, reacting until the raw materials completely react, cooling to room temperature, adding ethyl acetate and water into the reaction solution, separating out an organic phase, and concentrating to obtain 4-carbonyl-quinazolino [6.7-6] -12-crown-4; the feeding amount molar ratio of the 6-amino-3, 4- (benzo-12-crown-4) ethyl benzoate hydrochloride to the ammonium formate is 1: 3; the certain temperature is 120-170 ℃.
5. The process for the preparation of icotinib key intermediate according to claim 1, characterized in that: the crown ether cyclization reaction in the step (1') is as follows: adding a certain amount of N-Boc-3, 4-dihydroxyaniline and anhydrous barium hydroxide into N, N-dimethylformamide, heating to a certain temperature under the protection of nitrogen, stirring for a period of time, then slowly adding an N, N-dimethylformamide solution dissolved with triethylenetetramine (p-toluenesulfonate), continuing the reaction at the temperature until the raw materials are completely reacted, evaporating N, N-dimethylformamide in vacuum, adding the concentrate into dichloromethane, adding trifluoroacetic acid and concentrated sulfuric acid, stirring for a period of time at the temperature of 0-10 ℃, adding water, filtering, separating out an organic phase, extracting the reaction solution with dichloromethane for multiple times in a water phase, combining the organic phases, adjusting the pH value to be neutral with saturated sodium hydroxide, separating out the organic phase, and concentrating to obtain 3,4- (benzo-12-crown-4) aniline; the feeding amount molar ratio of the N-Boc-3, 4-dihydroxyaniline to anhydrous barium hydroxide is 1: 1-1.2; the certain temperature is 70-100 ℃.
6. The process for the preparation of icotinib key intermediate according to claim 1, characterized in that: the chlorination reaction in the step (1') is as follows: dissolving a certain amount of 3,4- (benzo-12-crown-4) aniline in dichloroethane, stirring for dissolving, adding N-chlorosuccinimide, slowly heating to 70 ℃, reacting for a period of time, monitoring the reaction completion of raw materials by TLC, cooling to room temperature, filtering the reaction solution, pouring the filtrate into ice water, adding saturated sodium hydroxide solution, separating out an organic phase, adjusting the pH of the organic phase to be neutral by using dilute hydrochloric acid solution, separating out the organic phase again, drying by using anhydrous magnesium sulfate, and concentrating to obtain 6-chloro-3, 4- (benzo-12-crown-4) aniline; the feeding amount molar ratio of the 3,4- (benzo-12-crown-4) aniline to the N-chlorosuccinimide is 1: 1.5.
7. The process for the preparation of icotinib key intermediate according to claim 1, characterized in that: the quinoline cyclization reaction in the step (1') is as follows: adding a certain amount of 6-amino-3, 4- (benzo-12-crown-4) benzamide into triethyl orthoformate, heating until the reflux raw materials react completely, cooling to room temperature, filtering to obtain a crude product, and washing a filter cake with methyl tert-butyl ether to obtain the 4-carbonyl-quinazolino [6.7-6] -12-crown-4.
8. The process for the preparation of icotinib key intermediate according to claim 1, characterized in that: the quinoline cyclization reaction in the step (2) is as follows: adding a certain amount of 4-carbonyl-quinazolino [6.7-6] -12-crown-4 and N, N-dimethylformamide into thionyl chloride, stirring uniformly, slowly heating up and refluxing, carrying out thionyl chloride with toluene after the reaction is finished, washing the obtained solid with toluene, and drying to obtain 4-chloro-quinazolino [6.7-6] -12-crown-4.
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