Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the technical problem of the prior art and provides a preparation method of 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline hydrochloride (compound IV).
The invention also aims to solve the technical problem of providing a preparation method of 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline (compound V).
The invention finally aims to solve the technical problem of providing a novel preparation method of (E) -N- [4- (3-ethynylphenyl) amino-3-cyano-7-ethoxy-6-quinolyl ] -4- (dimethylamino) -2-butenamide (compound I), which has the advantages of easily obtained raw materials, controllable product quality, low production cost, simple process, environmental protection and economy.
In order to solve the first technical problem, the invention discloses a preparation method of 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline and hydrochloride thereof (shown in a formula IV), which comprises the following steps: carrying out heating substitution reaction on N- (4-chloro-3-cyano-7-ethoxyquinoline-6-yl) acetamide shown in a formula II and m-aminophenylacetylene under the condition of taking N-propanol as a reaction solvent to obtain a solution containing 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline hydrochloride shown in a formula IV;
wherein the feeding amount molar ratio of the N- (4-chloro-3-cyano-7-ethoxyquinoline-6-yl) acetamide to the m-aminophenylacetylene is 1: 0.6-1.6, further 1: 0.8-1.3, and further 1: 1-1.3.
Wherein the feeding amount of the N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide and the N-propanol is 1: 4-60, preferably 1: 8-32, and more preferably 1: 10-20 in weight ratio.
Wherein the temperature of the heating substitution reaction is more than 50 ℃, preferably 60-100 ℃, more preferably 80-100 ℃, more preferably 90-98 ℃, and more preferably boiling; the time of the heating substitution reaction is 2-5h, and is preferably 3 h.
Preferably, after the substitution reaction is finished, cooling to 0-40 ℃, separating and drying to obtain 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline hydrochloride; further, the separation method is preferably a centrifugal separation method, and the solid is washed and dried by using normal propyl alcohol after separation.
Wherein the temperature is reduced to 0-40 ℃, further 0-10 ℃ or 5-15 ℃, and further 0-5 ℃.
In order to solve the second technical problem, the invention discloses a preparation method of 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline shown as a formula V, which comprises the following steps: mixing 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline or hydrochloride thereof with n-propanol and concentrated hydrochloric acid to carry out a first reaction to obtain a first reaction solution; adding water into the first reaction solution to carry out a second reaction to obtain a solution containing 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline shown in the formula V;
wherein, the concentration range of hydrochloric acid in the concentrated hydrochloric acid is 3.0N-12.0N, preferably 8.0N-12.0N, and preferably the concentration range is a water saturated solution of hydrogen chloride.
Wherein, the 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline or the hydrochloride thereof is prepared by any method in the prior art; preferably, it is prepared according to the first technical scheme of the invention.
Wherein the feeding weight ratio of the 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline or the hydrochloride thereof to the n-propanol is 1: 5-30, and preferably 1: 1-20.
Wherein the charging weight of the 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline or the hydrochloride thereof and the concentrated hydrochloric acid is 1: 1-6, and further 1: 2-3.
Wherein the mass ratio of the concentrated hydrochloric acid to the water is 1: 1.5-3.
Wherein the temperature of the first reaction is 70 ℃ to 100 ℃, preferably 80 ℃ to 97 ℃, and more preferably 80 ℃ to 90 ℃.
Wherein the reaction time of the first reaction is 1 to 4 hours, preferably 1.5 to 3 hours.
Wherein the temperature of the second reaction is 70 ℃ to 100 ℃, preferably 80 ℃ to 97 ℃, and more preferably 80 ℃ to 90 ℃.
Wherein the reaction time of the second reaction is 1 to 3 hours.
Wherein, after the second reaction is finished, the temperature is reduced, the mixture is stirred and centrifuged, potassium carbonate aqueous solution is added into the obtained solid for reaction, and after the reaction is preferably finished, the mixture is filtered and dried to obtain the 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline.
Wherein the temperature reduction is 0-40 ℃, and the stirring time is 1-2 hours.
Wherein the temperature is reduced to 0-40 ℃, and further to 0-10 ℃ or 1-15 ℃.
Wherein the feeding weight ratio of the 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline or the hydrochloride thereof to the potassium carbonate is 1: 0.5-4, preferably 1: 1-2; the feeding mass ratio of potassium carbonate to water in the potassium carbonate water solution is 1: 5-20, preferably 1: 10-15, and further preferably 1: 12-13; the reaction temperature is 10-50 ℃, and preferably 20-30 ℃; the reaction time is 1-3 hours.
In order to solve the third technical problem, the invention discloses a preparation method of an EGFR molecular targeted antitumor drug, wherein the EGFR molecular targeted antitumor drug is (E) -N- [4- (3-ethynylphenyl) amino-3-cyano-7-ethoxy-6-quinolyl 1-4- (dimethylamino) -2-butenamide shown in formula I, and the preparation method comprises the following steps: after the trans-4-dimethylamino crotonate reacts with an acylation reagent, the obtained product is subjected to condensation reaction with 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline to obtain a solution containing (E) -N- [4- (3-ethynylphenyl) amino-3-cyano-7-ethoxy-6-quinolyl ] -4- (dimethylamino) -2-butenamide;
specifically, the method comprises the following steps:
(1) carrying out substitution reaction on N- (4-chloro-3-cyano-7-ethoxyquinoline-6-yl) acetamide (compound II) and m-aminophenylacetylene (compound III) to obtain a compound IV;
(2) under the acidic condition, the compound IV is hydrolyzed to obtain 3-cyano-6-amino-7-ethyoxyl-4 (3-ethynylanilino) quinoline (compound V);
(3) after the trans-4-dimethylamino crotonate (compound VI) and an acylation reaction reagent are subjected to acylation reaction, the product is subjected to condensation reaction with 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline (compound V) to obtain (E) -N [4- (3-ethynylphenyl) amino-3-cyano-7-ethoxy-6-quinolyl ] -4- (dimethylamino) -2-butenamide (compound I).
The reaction equation is as follows:
in the step (1), the heating substitution reaction temperature is more than 50 ℃, preferably 60-100 ℃, more preferably 80-100 ℃, further preferably 90-98 ℃, and further preferably boiling; the time of the heating substitution reaction is 2 to 5 hours, and is preferably 3 hours.
In the step (1), the substitution reaction solvent is n-propanol.
In the step (1), the molar ratio of the N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide (compound II) to the m-aminophenylacetylene (compound III) is 1:0.6 to 1.6, further 1:0.8 to 1.3, further 1: 1.1 to 1.2, and most preferably 1: 1.1.
In the step (1), the feeding amount of the N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide (compound II) and the N-propanol is 1: 4-60, preferably 1: 8-32, and more preferably 1: 10-20 by weight ratio.
In the step (1), after the substitution reaction is finished, cooling to 0-40 ℃, separating and drying to obtain 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline hydrochloride; further, the separation method is preferably a centrifugal separation method, and after separation, the solid is washed and dried by using normal propyl alcohol.
In the step (2), under an acidic condition, the compound IV is subjected to hydrolysis reaction to obtain 3-cyano-6-amino-7-ethoxy-4 (3-ethynylanilino) quinoline (compound V), and specifically, 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline hydrochloride, n-propanol and concentrated hydrochloric acid are mixed for first reaction, water is added for second reaction, and a solution containing the 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline shown in the formula V is obtained.
Wherein the feeding weight ratio of the 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline hydrochloride to the n-propanol is 1: 5-30, preferably 1: 1-20; the feeding weight of the 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline hydrochloride and concentrated hydrochloric acid is 1: 1-6, and further 1: 2-3; the feeding mass ratio of the concentrated hydrochloric acid to the water is 1: 1.5-3; the temperature of the first reaction is 70-100 ℃, preferably 80-97 ℃, and further preferably 80-90 ℃; the reaction time of the first reaction is 1 to 4 hours, preferably 1.5 to 3 hours; the temperature of the second reaction is 70-100 ℃, preferably 80-97 ℃, and further preferably 80-90 ℃; the reaction time of the second reaction is 1 to 3 hours.
And after the second reaction is finished, cooling, stirring, centrifuging, adding a potassium carbonate aqueous solution into the obtained solid, reacting, filtering after the reaction is finished, and drying to obtain the 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline. Preferably, the temperature reduction is 0-40 ℃, and preferably 0-20 ℃; the stirring time is 1-2 hours.
Wherein the feeding weight ratio of the 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline hydrochloride (compound IV) to the potassium carbonate is 1: 1-2; the feeding ratio of potassium carbonate to water in the potassium carbonate water solution is 1: 5-20, and preferably 1: 5-10; the reaction temperature is 10-50 ℃, and preferably 20-30 ℃; the reaction time is 1-3 hours.
The concentration of hydrochloric acid in the concentrated hydrochloric acid is in the range of 3.0N-12.0N, preferably 4.0N-12.0N, and is preferably a saturated aqueous solution of hydrogen chloride.
(3) After the trans-4-dimethylamino crotonate (compound VI) and an acylation reaction reagent are subjected to acylation reaction, the product is subjected to condensation reaction with 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline (compound V) to obtain (E) -N [4- (3-ethynylphenyl) amino-3-cyano-7-ethoxy-6-quinolyl ] -4- (dimethylamino) -2-butenamide (compound I).
In the step (3), the acylating reagent is an amide linking reagent, preferably oxalyl chloride, thionyl chloride or phosphorus trichloride, and more preferably oxalyl chloride; the temperature of the acylation reaction is 0-40 ℃, preferably 20-30 ℃, and the reaction time is 1-3 hours, preferably 1 hour; the acylation reaction solvent is an aprotic solvent, preferably tetrahydrofuran, acetonitrile, dioxane or N, N-dimethylformamide, more preferably tetrahydrofuran.
Preferably, an acylating reagent is dripped into a mixed solution of trans-4-dimethylamino crotonate and a first solvent, then a second solvent is dripped, and the mixture is stirred for reaction to obtain a reaction solution; wherein in the mixed solution of the trans-4-dimethylamino crotonate and the first solvent, the mass ratio of the trans-4-dimethylamino crotonate to the first solvent is 1: 3.5-3.6; the first solvent is preferably tetrahydrofuran; the dosage ratio of the second solvent to the trans-4-dimethylamino crotonate is 59-80 mL/kg; the molar ratio of the acylating agent to the trans-4-dimethylamino crotonate is 1:1.
In the step (3), the condensation reaction temperature is-20-30 ℃, preferably-20-0 ℃; the time of the condensation reaction is 0.5-5 h; the solvent of the condensation reaction is acetonitrile, N-methyl pyrrolidone or tetrahydrofuran, and N-methyl pyrrolidone is preferred.
Preferably, cooling the reaction liquid obtained by the acylation reaction, dropwise adding a solution consisting of a condensation reaction solvent and a compound V, dropwise adding water after the reaction reaches the end point, then adding an alkaline water solution to adjust the pH value to 9-12, stirring for reaction, centrifuging, washing and drying the reaction liquid to obtain the compound V; wherein the amount of the condensation reaction solvent is 5.15kg/kg of the compound V; the amount of water used was 3kg/kg of compound V; the stirring reaction is carried out for 1.5-2 h at the temperature of 20-40 ℃.
In the step (3), after the condensation reaction is finished, adding an alkaline aqueous solution into the reaction solution to adjust the pH to 9-12, preferably 10-11, and separating out a compound I; the alkaline aqueous solution is any one or more aqueous solutions of potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate and sodium hydroxide.
In the step (3), the molar ratio of the trans-4-dimethylamino crotonate (compound VI) to the acylating agent to the 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline (compound V) is 1-2: 1, preferably 2: 1.
In the step (3), the compound (V) and the compound (VI) are condensed to obtain the compound (I), the usable condensation reaction conditions include the combination of the carboxylic acid compound (VI) with an acylating agent to form an acyl halide, or with sulfonyl chloride and chloroformate to form a mixed anhydride compound, a carbodiimide compound CDI, EDC, DCC or other condensing agent and activating agents DMAP, HOBt, HOAt, and the preferable preparation method is to prepare the acyl chloride by activating the compound (VI).
The preparation method of 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline or hydrochloride thereof according to any one of the above embodiments does not include a catalyst, such as methanesulfonic acid, during the reaction.
Has the beneficial effects that: compared with the prior art, the invention has the following advantages:
(1) the preparation method has the advantages of easily available raw materials, simple process, low production cost, economy, environmental protection, suitability for industrial production and the like.
(2) The N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide (compound II), m-aminophenylacetylene (compound III), and trans-4-dimethylaminocrotonate (compound VI) employed in the present invention are readily available commercially.
(3) According to the invention, no catalyst is used in the process of preparing 3-cyano-6-acetamido-7-ethoxy-4- (3-ethynylanilino) quinoline or hydrochloride thereof from N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide (compound II), so that the reaction time can be effectively shortened and the reaction efficiency can be improved under the action of N-propanol, and the compound IV can be separated.
(4) According to the invention, in the process of preparing (E) -N [4- (3-ethynylphenyl) amino-3-cyano-7-ethoxy-6-quinolyl ] -4- (dimethylamino) -2-butenamide (compound I) from 3-cyano-6-amino-7-ethoxy-4- (3-ethynylanilino) quinoline (compound V), the addition sequence of hydrochloric acid and water is changed, so that the yield can be effectively improved, and the content of impurities can be reduced.
Detailed Description
The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
In the following examples, concentrated hydrochloric acid is described as a water-saturated solution of hydrogen chloride.
Example 1-1: preparation of Compound IV
1.155kg of N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide and 18.48kg of n-propanol are added into a 50L reaction kettle and stirred uniformly; adding 0.52kg of m-aminophenylacetylene (the molar ratio of the compound III to the compound II is 1.1: 1); heating to 90-95 ℃, reacting for 3 hours to reach the end point, cooling to 0-5 ℃, centrifuging, washing the solid with n-propanol, and drying to obtain 1.544kg of product in the form of hydrochloride with the yield of 96% and the HPLC test content of 99.58%.
Examples 1 to 2: preparation of Compound IV
Adding 1.500kg of N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide and 18.00kg of n-propanol into a 50L reaction kettle, and uniformly stirring; adding 0.789kg of m-aminophenylacetylene (the molar ratio of the compound III to the compound II is 1.3: 1); heating to 85-90 ℃, reacting for 3 hours to reach the end point, cooling to 10-15 ℃, centrifuging, washing the solid with n-propanol, and drying to obtain 2.015kg of product with 99.46% of content and 96% of yield.
Examples 1-3 preparation of compound IV:
adding 1.00kg of N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide and 15.00kg of n-propanol into a 50L reaction kettle, and uniformly stirring; adding 0.325kg of m-aminophenylacetylene (the molar ratio of the compound III to the compound II is 0.8: 1); heating to boiling reflux, reacting for 2.7 hours to reach the end point, cooling to 0-10 ℃, centrifuging, washing the solid with n-propanol, and drying to obtain 1.336kg of the product with the yield of 95% and the content of 99.53%.
Examples 1-4 preparation of compound IV:
adding 3.00kg of N- (4-chloro-3-cyano-7-ethoxyquinoline-6-yl) acetamide compound and 48.00kg of n-propanol into a 100L reaction kettle, and uniformly stirring; adding 1.35kg of m-aminophenylacetylene; heating to 90-95 ℃, reacting for 3 hours to reach the end point, cooling to 0-5 ℃, centrifuging, washing the solid with n-propanol, and drying to obtain 4.05kg of product with the yield of 96% and the content of 99.61%.
EXAMPLE 2-1 preparation of Compound V
Adding 1.300kg of the compound IV prepared in the embodiment 1-3 and 20.00kg of n-propanol into a 50L reaction kettle, stirring, raising the temperature to 85-90 ℃, adding 3.263kg of concentrated hydrochloric acid, reacting at 85-90 ℃ for 3 hours to reach a balance point, adding 8.32kg of water, reacting at 85-90 ℃ for 2.5 hours to reach an end point, cooling to 0-10 ℃, stirring for 2 hours, centrifuging, and washing; the obtained solid was stirred at 10-20 ℃ for 3 hours in a solution of 1.313kg of potassium carbonate and 16.90kg of water, centrifuged, washed and dried to obtain 0.99kg of a product with a yield of 95% and a content of 99.14% containing 0.33% of the impurity compound IV.
EXAMPLE 2-2 preparation of Compound V
Adding 2.00kg of 3-cyano-6-methylacetamido-7-ethoxy-4- (3-ethynylanilino) quinoline and 25.60kg of n-propanol which are the compounds IV prepared by the method in the embodiment 1-1 into a 50L reaction kettle, stirring, raising the temperature to 80-90 ℃, adding 5.02kg of concentrated hydrochloric acid, reacting for 2.5 hours at 80-90 ℃ to reach the equilibrium point, adding 12.80kg of water, reacting for 2 hours at 80-90 ℃, cooling to 0-5 ℃, stirring for 2 hours, centrifuging and washing; the solid obtained was stirred at 20 ℃ to 30 ℃ for 2 hours in a solution of 1.313kg of potassium carbonate and 16.90kg of water, centrifuged, washed and dried to obtain 1.48kg of a product with a yield of 92% and a content of 99.17%, with the compound IV as an impurity of 0.43%.
Examples 2-3 preparation of Compound V
Adding 4.04kg of compound IV prepared in the embodiment 1-4 and 51.71kg of n-propanol into a 200L reaction kettle, stirring, raising the temperature to 80-90 ℃, adding 10.14kg of concentrated hydrochloric acid, reacting at 80-90 ℃ for 2.5 hours to reach a balance point, adding 25.85kg of water, reacting at 80-90 ℃ for 2 hours to reach an end point, cooling to 10-15 ℃, stirring for 2 hours, centrifuging, and washing; the solid obtained is stirred for 1.5 hours at 20-30 ℃ by using a solution consisting of 4.08kg of potassium carbonate and 52.52kg of water, and then the product 3.09kg is obtained after centrifugal filtration, washing and drying. The content was 99.21%, the content of compound IV as an impurity was 0.40%, and the yield was 94%.
EXAMPLE 3-1 preparation of Compound I
Mixing and stirring 1.515kg (9.14mol) of compound VI and 5.34kg of tetrahydrofuran, dropwise adding 1.155kg (9.1mol) of oxalyl chloride at the temperature of 10-20 ℃, dropwise adding 90ml of N, N-dimethylformamide after completing the dropwise adding, and keeping the temperature at 20-30 ℃ and stirring for 1 hour after completing the dropwise adding; cooling to-20 ℃ to-10 ℃, dripping solution consisting of 7.725kg of N-methyl pyrrolidone and 1.500kg (4.57mol) of compound V, reacting for 1 hour until the end point, dripping 4.5kg of water, dripping solution consisting of 1.665kg of sodium hydroxide and 70.5kg of water, stirring for 2 hours at 20-30 ℃, centrifuging, washing and drying to obtain 1.934kg of product, wherein the yield is 96.3%. The content was 97.68%, the impurity was 0.32% in terms of compound IV and the impurity was 0.28% in terms of compound V.
EXAMPLE 3-2 preparation of Compound I
Mixing and stirring a compound VI, namely 0.859kg (the mole number is 5.18mol) of trans-4-dimethylamino crotonate and 3.026kg of tetrahydrofuran, dropwise adding 0.654kg (the mole number is 5.18mol) of oxalyl chloride (keeping the temperature between 10 and 20 ℃), dropwise adding 51ml of N, N-dimethylformamide after the oxalyl chloride is dropwise added, and stirring for 1 hour under the condition of heat preservation at the temperature between 20 and 30 ℃; cooling to-10 ℃, dripping solution consisting of 4.3785kg of N-methyl pyrrolidone and 0.85kg of compound V (2.59mol), reacting for 1.25 hours to reach the end point, dripping 2.55kg of water, dripping solution consisting of 0.944kg of sodium hydroxide and 39.95kg of water, stirring for 1.5 hours at 30-40 ℃, centrifuging, washing and drying to obtain 1.090kg of a product, wherein the yield is 95.8%. The content was 97.42%, the impurity was 0.28% in terms of compound IV and 0.27% in terms of compound V.
Examples 3-3 preparation of Compound I
Mixing and stirring 1.515kg (the mole number is 9.14mol) of the compound VI and 5.34kg of tetrahydrofuran, dropwise adding 1.155kg (9.1mol) of oxalyl chloride (keeping the temperature between 10 and 20 ℃), dropwise adding 120ml of N, N-dimethylformamide after completing the oxalyl chloride dropwise addition, and keeping the temperature between 10 and 20 ℃ and stirring for 1 hour after completing the oxalyl chloride dropwise addition; cooling to-20 to-0 ℃, dripping solution consisting of 7.725kg of N-methyl pyrrolidone and 1.500kg of compound V (4.56mol), reacting for 1 hour until the end point, dripping 4.5kg of water, dripping solution consisting of 1.665kg of sodium hydroxide and 70.5kg of water, stirring for 2 hours at 20 to 30 ℃, centrifuging, washing and drying to obtain 1.990kg of product, wherein the yield is 99.1%. The content was 97.18%, the impurity was 0.23% in terms of compound IV and the impurity was 0.30% in terms of compound V.
EXAMPLES 1-1 preparation of Compound IV
The preparation method of 3-cyano-6-formylamino-7-ethoxy-4- (3-ethynylanilino) quinoline comprises the following steps: adding 5.00g N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide compound III to compound II in a ratio of 1: 1.1)) and 95mL of ethanol into a 250mL reaction bottle, and uniformly stirring; 2.24g of m-aminophenylacetylene is added; raising the temperature to 90-95 ℃, reacting for 7 hours to reach the end point, cooling to 0-5 ℃, centrifuging, washing solids, and drying to obtain 6.1g of a product with the content of 93.25 percent by HPLC test.
The experiment adopts ethanol as a reaction solvent, and has high impurity content, low content and low yield.
EXAMPLES 1-2 preparation of Compound IV
5.00g N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide (molar ratio: compound III to compound II 1.1: 1) and 95ml isopropanol were added to a 250ml reaction flask and stirred uniformly; 2.24g of m-aminophenylacetylene is added; heating to 90-95 ℃, reacting for 6 hours to the end point, cooling to 0-5 ℃, centrifuging, washing solids, and drying to obtain 7.01g of a product with the content of 72.61%.
The experiment adopts isopropanol as a reaction solvent, so that the impurity is high, the HPLC test content is low, and the yield is low.
EXAMPLES 1-3 preparation of Compound V
Adding N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide (249.5g, 0.863mol, 1.0equiv) and 3.0L ethanol into a 10L reaction flask, and stirring uniformly; dissolving m-aminophenylacetylene (111.4g, 0.951mol, 1.1equiv) in 3.0L ethanol, and placing into a reaction flask; methanesulfonic acid (22.5ml, 0.35mol) was added with stirring, the reaction was carried out at 84 ℃ for 6 hours, the reaction mixture was cooled to room temperature, diluted hydrochloric acid (2.0L, 4.0mol/L) was added with stirring, the reaction mixture was heated to 80 ℃ and reacted for 23 hours, the temperature of the reaction mixture was cooled to 15 ℃, crystallization was carried out for 11 hours, suction filtration was carried out, the filter cake was suspended with 95% ethanol (6L), an aqueous potassium carbonate solution (4.0L, 1mol/L) was added with stirring, the mixture was stirred at room temperature for 1 hour, filtration was carried out, the filter cake was washed twice with 1.0L of water and dried at 50 ℃ for 10 hours, and 222.5g of yellow solid powder was obtained with a yield of 78.5%. HPLC detection shows that the content of the target product (compound V) is 98.29%, and the content of the compound IV as an impurity is 1.64%.
EXPERIMENTAL EXAMPLE 2-2 preparation of Compound V
Adding 1.40kg of the compound IV prepared in the example 1-1 and 17.92kg of n-propanol into a 50L reaction kettle, stirring, raising the temperature to 85-90 ℃, adding 3.514kg of concentrated hydrochloric acid and 8.96kg of water (the feeding ratio of the compound IV to the concentrated hydrochloric acid is 1: 2.5, and the ratio of the concentrated hydrochloric acid to the water is 1: 2.55), reacting for 3 hours at 85-90 ℃, reaching the reaction end point, cooling to 0-10 ℃, stirring for 2 hours, centrifuging, and washing; the solid thus obtained was stirred at 10 ℃ to 20 ℃ for 5 hours in a solution of 1.414kg of potassium carbonate (feed ratio of compound IV to potassium carbonate: 1.01, ratio of potassium carbonate to water: 1: 12.87) and 18.20kg of water, centrifuged, washed and dried to give 0.983kg of product. 98.10%, the content of compound IV as an impurity was 1.03%. The yield thereof was found to be 87.6%.
EXAMPLES 2-3 preparation of Compound V
2.00kg of the compound IV prepared in the embodiment 1-2 and 20.60kg of n-propanol are added into a 50L reaction kettle and stirred, the temperature is raised to 80-90 ℃, 4.02kg of concentrated hydrochloric acid and 8.80kg of water are added to react for 3 hours at 80-90 ℃ until the reaction end point is reached, the temperature is lowered to 0-10 ℃, the mixture is stirred for 2 hours, and the mixture is centrifuged and washed; the obtained solid is stirred for 3 hours at the temperature of 20-30 ℃ by using a solution consisting of 2.52kg of potassium carbonate and 20.00kg of water, and then the product 1.41kg is obtained after centrifugation, washing and drying. The yield was 87.5%, the content was 98.44%, and the content of compound IV as an impurity was 1.1%.
EXPERIMENTAL EXAMPLE 3-1 preparation of Compound I
Mixing and stirring compound VI, namely 1.01kg (6.09mol) of trans-4-dimethylamino crotonate and 3.56kg of tetrahydrofuran, dropwise adding 0.77kg (6.07mol) of oxalyl chloride (keeping the temperature between 10 and 30 ℃), dropwise adding 60ml of N, N-dimethylformamide after the oxalyl chloride is dropwise added, and stirring for 1 hour under the condition of keeping the temperature between 20 and 30 ℃; the temperature is reduced to minus 20 ℃ to minus 10 ℃, 5.15kg of N-methyl pyrrolidone and 1.00kg of solution consisting of the compound V (3.04mol) prepared in the example 2-3 are dripped in, 3kg of water is dripped when the reaction reaches the end point, 1.11kg of solution consisting of sodium hydroxide and 47kg of water is dripped in, the solution is stirred for 2 hours at the temperature of 20 ℃ to 30 ℃, and the product is centrifuged, washed and dried to obtain 1.185kg of product with the yield of 88.5 percent. The content was 97.62%, the impurity was 1.07% in terms of compound IV and 0.22% in terms of compound V.
The present invention provides a method and a concept for preparing an EGFR molecule targeted antitumor drug, and a method and a way for implementing the technical scheme are numerous, and the above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, a plurality of modifications and embellishments can be made without departing from the principle of the present invention, and these modifications and embellishments should also be regarded as the protection scope of the present invention. All the components not specified in the present embodiment can be realized by the prior art.