CN105399688A - Gefitinib preparation method - Google Patents

Abstract

The invention discloses a preparation method of gefitinib, which is characterized in that the intermediate quinazoline-4-one is chlorinated into 4-chloroquinazoline with a chlorinating agent, and the solvent and unreacted Chlorinating agent, do not separate and purify the product, directly add alkali, N-bromopropylmorpholine and fluorochloroaniline for the second reaction, add solvent to precipitate the crude product after the reaction, and obtain pure gefitinib after recrystallization and purification . The invention adopts the "one-pot synthesis" method, has simple preparation process, easy operation, high total yield, high yield and purity, low production cost, easy industrial production, and strong practicability.

Description

A kind of preparation method of gefitinib

technical field

The invention belongs to the preparation of organic compounds, and relates to a preparation method of gefitinib. The gefitinib prepared by the invention is used as an anticancer drug, and is especially suitable for treating advanced or metastatic non-small cell lung cancer.

Background technique

Gefitinib (gefitinib), the chemical name is 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, is Aspen An oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor developed by Asrazeneca is used as a drug for the treatment of advanced non-small cell lung cancer (NSCLC). The drug was first launched in Japan in July 2002, and was approved as a third-line monotherapy in the United States and Australia in May 2003 for the treatment of advanced non-small cell lung cancer. Entered China in 2005, it is used for the treatment of locally advanced or metastatic non-small cell lung cancer who have received platinum-based antineoplastic drugs and docetaxel chemotherapy and are ineffective and unsuitable for chemotherapy. The chemical structural formula of the drug gefitinib is shown as formula (I).

In the prior art, the methods for synthetically preparing gefitinib mainly include: (1) taking 3-hydroxyl-4-methoxybenzaldehyde as raw material, through nitrilation, condensation, nitration, reduction, condensation, and finally cyclization Get [WO2005070909]. (2) Using 2-nitro-4-methoxy-5-(3-morpholinopropoxy)benzonitrile as raw material, hydrogenation and condensation, and finally Dimroth rearrangement [CN102120731A]. (3) Using 3-hydroxy-4-methoxybenzaldehyde as a raw material, it is prepared through nitrilation, condensation, nitration, hydrolysis, reduction, cyclization, and chlorination and condensation [China Pharmaceutical Industry Journal, 2008, 3( 6): 401-3]. (4) It is prepared from 3,4-dimethoxy-6-aminobenzoic acid through cyclization, demethylation, acetylation, chlorination, amination, hydrolysis and condensation [US5770599]. Cao Xiaofeng et al. (Shandong Chemical Industry, 2014, 43 (5): 47-8) in the last few steps of the synthesis of the drug, by chlorinating the intermediate quinazoline-4-one into the corresponding 4-chloroquinazoline, and then In the presence of a base, it reacts twice with the side chain of morpholine and the side chain of fluorochloroaniline, and converts it into the final product gefitinib; however, the reaction activity of this method is obviously reduced, the side reactions are increased, and the product yield is not good. The above-mentioned prior art methods all separate the chlorination reaction and the two side chain reactions, and need to deal with three-step reactions. There are longer reaction routes, more unit operations, lower product yields, and are unfavorable for industrial production. insufficient.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies in the above-mentioned prior art, and to provide a preparation method of gefitinib. The present invention uses the quinazolin-4-one intermediate as a raw material and adopts a "one-pot synthesis" method, thereby providing an improved gefitinib with short synthetic route, low production cost, high yield and high purity method of preparation.

Content of the present invention is: a kind of preparation method of gefitinib is characterized in that the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent The dosage (that is, the amount in moles, the same hereinafter) is 1 to 50 times the moles of quinazolin-4-one, and the dosage of N,N-dimethylformamide (abbreviated as DMF) is the moles of quinazolin-4-one The amount of N-bromopropylmorpholine is 0.5 to 10 times of the number of moles of quinazolin-4-one, and the amount of chlorofluoroaniline is 0.5 to 10 times of the number of moles of quinazoline-4-one 10 times, the amount of base is 0.5 to 10 times the number of moles of quinazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine;

b. Preparation of chloride: Add N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one and solvent A in a reaction vessel (for example: in a three-necked flask), at 20 to 120 Under the temperature of ℃, stirring and reacting for 0.5～20h, after the completion of the reaction, solvent A and unreacted chlorinating agent were distilled off under reduced pressure, solvent B toluene was added to the residue, and concentrated under reduced pressure again (to remove solvent B, further remove solvent A and unreacted chlorinating agent), the operation of adding solvent B and then concentrating is repeated 3 times, and the mass consumption of solvent B toluene is 1 to 10 times of the residue quality at each time to obtain a solid;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of the solvent A is the quality of quinazolin-4-one 0 to 10 times;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 20-120° C. and stirred for 0.5-20 hours. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 10 to 100 times the amount of the substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 1.5 to 2.5 hours, filter, and obtain the crude product of gefitinib after drying the solid; Promptly make (white powdery solid) gefitinib product after recrystallization;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent D is 1 to 10 times the mass of the reacted material;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 1 to 100 times the mass of the crude product of gefitinib.

The preparation method of gefitinib described in the content of the present invention is characterized in that the steps are preferably:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent The dosage (that is, the amount in moles, the same below) is 10 to 30 times the moles of quinazolin-4-one, and the dosage of N,N-dimethylformamide (abbreviated as DMF) is the moles of quinazolin-4-one 0.5 to 2 times the number, the amount of N-bromopropylmorpholine is 1 to 3 times the molar number of quinazolin-4-one, and the amount of fluorochloroaniline is 1 to 3 times the molar number of quinazolin-4-one 3 times, the amount of base is 1 to 5 times the molar number of quinazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine;

b. Preparation of chlorides: Add N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one and solvent A in a reaction vessel (for example: in a three-necked flask), at 70 to 90 Under the temperature of ℃, stirring and reacting for 2-4 hours, after the reaction is completed, solvent A and unreacted chlorinating agent are removed by distillation under reduced pressure, solvent B toluene is added to the residue, and then concentrated by distillation under reduced pressure (to remove solvent B, further remove solvent A and unreacted chlorinating agent), the operation of adding solvent B and then concentrating is repeated 3 times, and the mass consumption of solvent B toluene is 2 to 5 times of the residue quality at each time to obtain a solid;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of solvent A is the quality of quinazoline-4-one 0~3 times;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 80-100° C. and stirred for 2-6 hours. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 20 to 50 times the amount of the substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 1.5 to 2.5 hours, filter, and obtain the crude product of gefitinib after drying the solid; Promptly make (white powdery solid) gefitinib product after recrystallization;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent D is 2 to 5 times the mass of the reacted material;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 10 to 30 times that of the crude product of gefitinib.

In the content of the present invention: said water is preferably distilled water or deionized water.

The synthetic route of the present invention is as follows:

In the reaction formula: 1 is quinazolin-4-one, 2 is a chlorinating agent (chloride), 3 is N-bromopropylmorpholine, 4 is fluorochloroaniline, and 5 is the product gefitinib.

Compared with the prior art, the present invention has the following characteristics and beneficial effects:

(1) The present invention chlorinates the intermediate quinazoline-4-one into corresponding 4-chloroquinazoline, and directly adds alkali, N-bromopropylmorpholine side chain and fluorochloroaniline without separation and purification The side chain is added to the reactant system, and gefitinib is prepared in one step through the "one-pot synthesis method". The existing three-step reaction is combined in one step, which greatly saves unit operations, short synthetic route, high efficiency, and reduced production costs. ;

(2) Adopt the present invention, the yield after refining can reach 65%, product purity reaches 98.5%, the condition used for reaction is simple, easy to scale up production; And prior art is because reaction step number is many, and yield is generally lower than 50%, And the production cost is higher;

(2) Adopting the present invention, the preparation process is simple, the process is simple, easy to operate, the total yield is high, the product is easy to purify, easy to industrialized production, and has strong practicability.

detailed description

The embodiment given below intends to further illustrate the present invention, but can not be interpreted as limiting the protection scope of the present invention, those skilled in the art make some non-essential improvements and adjustments to the present invention according to the content of the above-mentioned present invention, still belong to protection scope of the present invention.

Example 1:

A preparation method of gefitinib, the steps are: add 2.0g DMF, 30mL thionyl chloride and 2.9g raw material 1 (quinazolin-4-one, 20mmol) into a three-neck flask, heat up to 80°C and stir for 3h. After the reaction was completed, the solvent and unreacted chlorinating agent were evaporated under reduced pressure, 20 mL of toluene was added to the residue, concentrated under reduced pressure, and repeated 3 times. The obtained solid was dissolved in 250 mL of DMF, and 8.3 g of K ₂ CO ₃ , 6.2 g of side chain 3 (bromopropylmorpholine) and 4.4 g of side chain 4 (fluorochloroaniline) were sequentially added, and the temperature was raised to 90° C. and stirred for 3 h. After the reaction was completed, cool to room temperature, slowly add 1000mL of water while stirring, continue to stir for 2h, filter and dry to obtain 6g of crude gefitinib. The crude product was recrystallized from ethyl acetate to obtain 5.8 g of white powdery solid gefitinib.

Example 2:

A preparation method of gefitinib, the steps are: add 2.0g DMF, 30mL thionyl chloride and 2.9g raw material 1 (quinazolin-4-one, 20mmol) into a three-neck flask, heat up to 80°C and stir for 1h. After the reaction was completed, the solvent and unreacted chlorinating agent were evaporated under reduced pressure, 20 mL of toluene was added to the residue, concentrated under reduced pressure, and repeated 3 times. The obtained solid was dissolved in 200 mL of dichloromethane, 6.4 g of NaOH, 7.2 g of side chain 3 (bromopropylmorpholine) and 5.4 g of side chain 4 (fluorochloroaniline) were added successively, and the reaction was stirred under reflux for 8 h. After the reaction was completed, cool to room temperature, slowly add 1000 mL of toluene while stirring, continue stirring for 2 h, filter and dry to obtain 5.2 g of crude gefitinib. The crude product was recrystallized from ethanol to obtain 5 g of white powdery solid gefitinib.

Example 3:

A preparation method of gefitinib, the steps are: add 1.0g of DMF, 50g of phosphorus trichloride and 2.9g of raw material 1 (quinazolin-4-one, 20mmol) into a three-neck flask, reflux and stir for 3h. After the reaction was completed, the solvent and unreacted chlorinating agent were evaporated under reduced pressure, 20 mL of toluene was added to the residue, concentrated under reduced pressure, and repeated 3 times. The obtained solid was dissolved in 230 mL of ethyl acetate, 7.1 g of triethylamine, 6.9 g of side chain 3 (bromopropylmorpholine) and 4.8 g of side chain 4 (fluorochloroaniline) were added in sequence, and the reaction was stirred under reflux for 6 h. After the reaction was completed, cool to room temperature, slowly add 1000 mL of toluene while stirring, continue stirring for 2 h, and obtain 5.5 g of crude gefitinib after filtration and drying. The crude product was recrystallized from acetone to obtain 5.1 g of white powdery solid gefitinib.

Example 4:

A preparation method of gefitinib, the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, catalyst N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent The amount of N,N-dimethylformamide (abbreviated as DMF) is 1 time of the mole number of quinazoline-4-one 0.1 times of that, the consumption of N-bromopropylmorpholine is 0.5 times of the molar number of quinazoline-4-one, the consumption of fluorochloroaniline is 0.5 times of the molar number of quinazoline-4-one, and the consumption of alkali is 0.5 times the number of moles of quinazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, triethylamine;

b. Preparation of chloride: Add catalyst N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one in a reaction vessel (for example: a three-necked flask), and at a temperature of 20°C , stirred and reacted for 20h, concentrated under reduced pressure after the completion of the reaction, added solvent B toluene in the residue, then concentrated by distillation under reduced pressure, the operation of adding solvent B and concentrating was repeated 3 times, and the mass consumption of each solvent B toluene was the remaining 1 times the amount of substance, to obtain a solid;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 20° C. and stirred for 20 hours. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 10 times the amount of substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 1.5h, filter, and obtain the crude product of gefitinib after drying the solid; the crude product of gefitinib is recrystallized with solvent E Promptly make (white powdery solid) gefitinib product afterwards;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass consumption of the solvent D is 1 time of the mass of the material after the reaction;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 1 time of the mass of the crude product of gefitinib.

Example 5:

A preparation method of gefitinib, the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent Dosage (i.e. the amount in moles, the same hereinafter) is 50 times the moles of quinazoline-4-ones, and the amount of N,N-dimethylformamide (abbreviated as DMF) is 50 times the moles of quinazoline-4-ones 5 times, the consumption of N-bromopropyl morpholine is 10 times of the molar number of quinazoline-4-one, the consumption of fluorochloroaniline is 10 times of the molar number of quinazoline-4-one, and the consumption of alkali is 10 times of the molar number of quinazoline-4-one. 10 times the number of moles of oxazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, triethylamine;

b. Preparation of chlorides: Add catalyst N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one and solvent A in a reaction vessel (for example: a three-necked flask), at 120 ° C Under the temperature of 0.5 h, stir and react for 0.5h, after the reaction is completed, concentrate under reduced pressure, add solvent B toluene to the residue, then concentrate under reduced pressure distillation, the operation of adding solvent B and then concentrating is repeated 3 times, each time with solvent B toluene Quality dosage is 10 times of residue quality, obtains solid matter;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of the solvent A is the quality of quinazolin-4-one 10 times;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 120° C. and stirred for 0.5 h. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 100 times the amount of substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 1.5 to 2.5 hours, filter, and obtain the crude product of gefitinib after drying the solid; Promptly make (white powdery solid) gefitinib product after recrystallization;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass consumption of the solvent D is 10 times of the mass of the material after the reaction;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 100 times that of the crude product of gefitinib.

Embodiment 6:

A preparation method of gefitinib, the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, catalyst N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent The amount of N,N-dimethylformamide (abbreviated as DMF) is 25 times of the mole number of quinazoline-4-one 2.5 times of that, the consumption of N-bromopropylmorpholine is 5 times of the molar number of quinazoline-4-one, the consumption of fluorochloroaniline is 5 times of the molar number of quinazoline-4-one, and the consumption of alkali is 5 times the number of moles of quinazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine;

b. Preparation of chlorides: Add N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one and solvent A in a reaction vessel (for example: in a three-necked flask), at 70°C Under high temperature, stirring and reacting for 10 h, after the reaction was completed, the residue was concentrated by distillation under reduced pressure, and solvent B toluene was added to the residue, and then concentrated by distillation under reduced pressure. The operation of adding solvent B and then concentrating was repeated 3 times, each time using the mass The dosage is 5 times of the residue quality to obtain a solid;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of the solvent A is the quality of quinazolin-4-one 5 times;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 70° C. and stirred for 10 h. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 55 times the amount of substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 2h, filter, and obtain the crude product of gefitinib after drying the solid; after the crude product of gefitinib is recrystallized with solvent E Promptly make (white powdery solid) gefitinib product;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass consumption of the solvent D is 5 times of the mass of the material after the reaction;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 5 times that of the crude product of gefitinib.

Embodiment 7:

A preparation method of gefitinib, the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent Dosage (i.e. the amount in moles, the same hereinafter) is 10 times the moles of quinazoline-4-ones, and the amount of N,N-dimethylformamide (abbreviated as DMF) is 10 times the moles of quinazoline-4-ones. 0.5 times, the consumption of N-bromopropyl morpholine is 1 times of the mole number of quinazoline-4-one, the consumption of fluorochloroaniline is 1 time of the mole number of quinazoline-4-one, and the consumption of alkali is 1 time of the mole number of quinazoline-4-one. 1 times the number of moles of oxazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine;

b. Preparation of chlorides: Add catalyst N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one and solvent A in a reaction vessel (for example: a three-necked flask), at 70°C Under the temperature of 4h, stirring reaction 4h, after the completion of the reaction, distillation and concentration under reduced pressure, solvent B toluene was added to the residue, and then concentrated by distillation under reduced pressure, the operation of adding solvent B and then concentrating was repeated 3 times, each time with solvent B toluene Quality dosage is 2 times of residue quality, obtains solid matter;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of the solvent A is the quality of quinazolin-4-one 0.5 times;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 80° C. and stirred for 6 hours. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 20 times the amount of substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 1.5h, filter, and obtain the crude product of gefitinib after drying the solid; the crude product of gefitinib is recrystallized with solvent E Promptly make (white powdery solid) gefitinib product afterwards;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass consumption of the solvent D is 2 times of the mass of the material after the reaction;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 10 times that of the crude product of gefitinib.

Embodiment 8:

A preparation method of gefitinib, the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent Dosage (i.e. the amount in moles, the same hereinafter) is 30 times the moles of quinazoline-4-ones, and the amount of N,N-dimethylformamide (abbreviated as DMF) is 30 times the moles of quinazoline-4-ones 2 times, the consumption of N-bromopropyl morpholine is 3 times of the molar number of quinazoline-4-one, the consumption of fluorochloroaniline is 3 times of the molar number of quinazoline-4-one, and the consumption of alkali is 3 times of the molar number of quinazoline-4-one. 5 times the number of moles of oxazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine;

b. Preparation of chlorides: Add catalyst N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one and solvent A in a reaction vessel (for example: a three-necked flask), at 90°C Under the temperature of 2h, stirring and reacting for 2h, after the completion of the reaction, distillation under reduced pressure was concentrated, solvent B toluene was added to the residue, and then concentrated by distillation under reduced pressure. The operation of adding solvent B and then concentrating was repeated 3 times, each time using solvent B toluene Quality dosage is 5 times of residue quality, obtains solid;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of the solvent A is the quality of quinazolin-4-one 3 times;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 100° C. and stirred for 2 hours. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 50 times the amount of substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 2.5h, filter, and obtain the crude product of gefitinib after drying the solid; the crude product of gefitinib is recrystallized with solvent E Promptly make (white powdery solid) gefitinib product afterwards;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass consumption of the solvent D is 5 times of the mass of the material after the reaction;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 30 times that of the crude product of gefitinib.

Embodiment 9:

A preparation method of gefitinib, the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent Dosage (i.e. the amount in moles, the same hereinafter) is 20 times the number of moles of quinazoline-4-one, and the amount of N,N-dimethylformamide (abbreviated as DMF) is 20 times the number of moles of quinazoline-4-one. 1.2 times, the consumption of N-bromopropyl morpholine is 2 times of the molar number of quinazoline-4-one, the consumption of fluorochloroaniline is 2 times of the molar number of quinazoline-4-one, and the consumption of alkali is 2 times of the molar number of quinazoline-4-one. 3 times the number of moles of oxazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine;

b. Preparation of chlorides: Add catalyst N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one and solvent A in a reaction vessel (for example: a three-necked flask), at 80°C Under the temperature of 3h, stirring reaction 3h, after the completion of the reaction, distillation and concentration under reduced pressure, solvent B toluene was added to the residue, and then concentrated by distillation under reduced pressure, the operation of adding solvent B and then concentrating was repeated 3 times, each time with solvent B toluene Quality dosage is 3.5 times of residue quality, obtains solid matter;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of the solvent A is the quality of quinazolin-4-one 1,5 times of;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 90° C. and stirred for 4 hours. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 35 times the amount of substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 2h, filter, and obtain the crude product of gefitinib after drying the solid; after the crude product of gefitinib is recrystallized with solvent E Promptly make (white powdery solid) gefitinib product;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass consumption of the solvent D is 3.5 times of the mass of the material after the reaction;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 20 times that of the crude product of gefitinib.

Example 10:

A preparation method of gefitinib, the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent Dosage (i.e. the amount in moles, the same hereinafter) is 15 times of the moles of quinazoline-4-ones, and the amount of N,N-dimethylformamide (abbreviated as DMF) is 15 times of the moles of quinazoline-4-ones. 0.8 times, the consumption of N-bromopropyl morpholine is 1.3 times of quinazoline-4-one moles, the consumption of fluorochloroaniline is 1.3 times of quinazoline-4-one moles, and the consumption of alkali is quinazoline-4-ones moles times. 1.5 times the number of moles of oxazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine;

b. Preparation of chlorides: Add catalyst N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one and solvent A in a reaction vessel (for example: a three-necked flask), at 80°C Under the temperature of 3h, stirring reaction 3h, after the completion of the reaction, distillation and concentration under reduced pressure, solvent B toluene was added to the residue, and then concentrated by distillation under reduced pressure, the operation of adding solvent B and then concentrating was repeated 3 times, each time with solvent B toluene Quality dosage is 3 times of residue quality, obtains solid;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of the solvent A is the quality of quinazolin-4-one 1 times of

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 90° C. and stirred for 4 hours. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 30 times the amount of substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 2h, filter, and obtain the crude product of gefitinib after drying the solid; after the crude product of gefitinib is recrystallized with solvent E Promptly make (white powdery solid) gefitinib product;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass consumption of the solvent D is 3 times of the mass of the material after the reaction;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 15 times that of the crude product of gefitinib.

Example 11:

A preparation method of gefitinib, the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent Dosage (i.e. the amount in moles, the same hereinafter) is 22 times the number of moles of quinazoline-4-ones, and the amount of N,N-dimethylformamide (abbreviated as DMF) is 22 times the number of moles of quinazoline-4-ones 0.5 to 2 times, the amount of N-bromopropylmorpholine is 2.2 times of the mole of quinazoline-4-one, the amount of fluorochloroaniline is 2.2 times of the mole of quinazoline-4-one, the amount of alkali 2 times the number of moles of quinazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine;

b. Preparation of chlorides: Add catalyst N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one and solvent A in a reaction vessel (for example: a three-necked flask), at 70°C Under the temperature of 4h, stirring reaction 4h, after the completion of the reaction, distillation and concentration under reduced pressure, solvent B toluene was added to the residue, and then concentrated by distillation under reduced pressure, the operation of adding solvent B and then concentrating was repeated 3 times, each time with solvent B toluene Quality dosage is 4 times of residue quality, obtains solid matter;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of the solvent A is the quality of quinazolin-4-one 2.3 times;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 80° C. and stirred for 6 hours. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 40 times the amount of substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 2h, filter, and obtain the crude product of gefitinib after drying the solid; after the crude product of gefitinib is recrystallized with solvent E Promptly make (white powdery solid) gefitinib product;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass consumption of the solvent D is 4 times of the mass of the material after the reaction;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 22 times that of the crude product of gefitinib.

Example 12:

A preparation method of gefitinib, the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent Dosage (i.e. the amount in moles, the same hereinafter) is 10 times of the moles of quinazoline-4-ones, and the amount of N,N-dimethylformamide (abbreviated as DMF) is 10 times of the moles of quinazoline-4-ones. 0.9 times, the consumption of N-bromopropyl morpholine is 1.8 times of quinazoline-4-one moles, the consumption of fluorochloroaniline is 1.8 times of quinazoline-4-one moles, and the consumption of alkali is quinazoline-4-ones moles times. 2 times the number of moles of oxazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine;

b. Preparation of chlorides: Add catalyst N,N-dimethylformamide (DMF for short), chlorinating agent, quinazolin-4-one and solvent A in a reaction vessel (for example: a three-necked flask), at 90°C Under the temperature of 3h, stirring reaction 3h, after the completion of the reaction, distillation and concentration under reduced pressure, solvent B toluene was added to the residue, and then concentrated by distillation under reduced pressure, the operation of adding solvent B and then concentrating was repeated 3 times, each time with solvent B toluene Quality dosage is 4 times of residue quality, obtains solid matter;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of the solvent A is the quality of quinazolin-4-one 0.5 times;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 90° C. and stirred for 2 hours. After the reaction was completed, cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 28 times the amount of substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 1.5 to 2.5 hours, filter, and obtain the crude product of gefitinib after drying the solid; Promptly make (white powdery solid) gefitinib product after recrystallization;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass consumption of the solvent D is 4 times of the mass of the material after the reaction;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 18 times that of the crude product of gefitinib.

Example 13:

A preparation method of gefitinib, the steps are:

a. Ingredients: raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide (DMF for short), N-bromopropylmorpholine, fluorochloroaniline, alkali, chlorinating agent Dosage (i.e. the amount in moles, the same hereinafter) is 20 times that of the moles of quinazoline-4-ones, and the amount of N,N-dimethylformamide (abbreviated as DMF) is 20 times the moles of quinazoline-4-ones. 1.2 times, the consumption of N-bromopropyl morpholine is 2 times of the molar number of quinazoline-4-one, the consumption of fluorochloroaniline is 2 times of the molar number of quinazoline-4-one, and the consumption of alkali is 2 times of the molar number of quinazoline-4-one. 2.5 times the number of moles of oxazolin-4-one;

Described chlorinating agent can be any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride;

The alkali can be any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine;

b, preparation of chloride: add catalyst N,N-dimethylformamide (abbreviated as DMF), chlorinating agent, quinazoline-4-one and solvent A in reaction vessel (for example: in three-necked flask), at 70～ Stir and react for 3 hours at a temperature of 90°C. After the reaction is completed, concentrate by distillation under reduced pressure, add solvent B toluene to the residue, and then concentrate by distillation under reduced pressure. The operation of adding solvent B and then concentrating is repeated 3 times, each time using solvent B The quality consumption of toluene is 3 times of residue quality, obtains solid;

The solvent A can be any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide (abbreviated as DMF), and the mass consumption of the solvent A is the quality of quinazolin-4-one 1 times;

c. Branching reaction: dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine (or called: bromopropylmorpholine) and fluorochloroaniline (or called: 3-chloro- 4-fluoroaniline), heated up to a reaction temperature of 80-100° C. and stirred for 4 hours. After the reaction was completed, it was cooled to room temperature to obtain the reacted material;

The solvent C can be any one of methylene chloride, toluene, ethyl acetate, N,N-dimethylformamide (DMF for short), butanol, and acetone, and the mass dosage of the solvent C is the solid 30 times the amount of substance;

d. Post-processing: under stirring (slowly) add solvent D to mix with the reacted material, then stir for 2h, filter, and obtain the crude product of gefitinib after drying the solid; after the crude product of gefitinib is recrystallized with solvent E Promptly make (white powdery solid) gefitinib product;

The solvent D can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass consumption of the solvent D is 3 times of the mass of the material after the reaction;

The solvent E can be any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 20 times that of the crude product of gefitinib.

In the foregoing embodiment: the water is distilled water or deionized water.

In above-mentioned embodiment: each raw material that adopts is commercially available product.

In the above-mentioned embodiments: in the percentages used, those not specified are all mass (weight) percentages or percentages known to those skilled in the art; the mass (weight) parts can be grams or kilograms.

Among the above-mentioned embodiments: the process parameters (temperature, time, concentration, etc.) in each step and the numerical values of the amounts of each component are within the range, and any point is applicable.

The content of the present invention and the technical content not specifically described in the above embodiments are the same as the prior art.

The present invention is not limited to the above-mentioned embodiments, and all of the contents of the present invention can be implemented and have the above-mentioned good effects.

Claims (3)

1. a preparation method for gefitinib, characterized in that the steps are: a, ingredients: take raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide, N-bromopropyl morpholine, fluorochloroaniline, alkali, the consumption of chlorinating agent is quinazoline 1 to 50 times the moles of lin-4-ones, the amount of N,N-dimethylformamide is 0.1 to 5 times the moles of quinazolin-4-ones, and the amount of N-bromopropylmorpholine is 0.5 to 10 times the moles of quinazoline-4-ones, the amount of fluorochloroaniline is 0.5 to 10 times the moles of quinazoline-4-ones, and the amount of base is 0.5 to 10 times the moles of quinazoline-4-ones 0.5 to 10 times; Described chlorinating agent is any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride; The alkali is any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine; b. Preparation of chloride: Add N,N-dimethylformamide, chlorinating agent, quinazolin-4-one and solvent A into the reaction vessel, and stir for 0.5-20 hours at a temperature of 20-120°C. After the reaction is completed, solvent A and unreacted chlorinating agent are removed by distillation under reduced pressure, solvent B toluene is added to the residue, and then concentrated by distillation under reduced pressure. The operation of adding solvent B and then concentrating is repeated 3 times, each time using solvent B toluene The mass dosage is 1 to 10 times of the residue mass to obtain a solid; The solvent A is any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide, and the mass dosage of the solvent A is 0 to 10 times the mass of quinazolin-4-one ; c. Branching reaction: Dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine and fluorochloroaniline in sequence, heat up to 20-120°C and stir for 0.5-20 hours at the reaction temperature. After completion, cool to room temperature to obtain the reacted material; The solvent C is any one of dichloromethane, toluene, ethyl acetate, N,N-dimethylformamide, butanol, and acetone, and the mass dosage of the solvent C is 10-10% of the solid matter. 100 times; d. Post-treatment: add solvent D to mix with the reacted material under stirring, then stir for 1.5-2.5h, filter, and dry the solid to obtain the crude product of gefitinib; the crude product of gefitinib is recrystallized with solvent E That is, the gefitinib product is obtained; The solvent D is any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent D is 1 to 10 times the mass of the reacted material; The solvent E is any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 1 to 100 times that of the crude product of gefitinib. 2. by the preparation method of gefitinib described in claim 1, it is characterized in that the steps are: a, ingredients: take raw materials quinazolin-4-one, chlorinating agent, N,N-dimethylformamide, N-bromopropyl morpholine, fluorochloroaniline, alkali, the consumption of chlorinating agent is quinazoline 10 to 30 times the moles of lin-4-ones, the amount of N,N-dimethylformamide is 0.5 to 2 times the moles of quinazolin-4-ones, and the amount of N-bromopropylmorpholine is 1 to 3 times the moles of quinazoline-4-ones, the amount of fluorochloroaniline is 1 to 3 times the moles of quinazoline-4-ones, and the amount of base is 1 to 3 times the moles of quinazolin-4-ones 1 to 5 times; Described chlorinating agent is any in sulfur oxychloride, phosphorus pentachloride, phosphorus trichloride and phosphorus oxychloride; The alkali is any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium tert-butoxide, and triethylamine; b. Preparation of chloride: Add N,N-dimethylformamide, chlorinating agent, quinazolin-4-one and solvent A into the reaction vessel, and stir for 2-4 hours at a temperature of 70-90°C. After the reaction is completed, solvent A and unreacted chlorinating agent are removed by distillation under reduced pressure, solvent B toluene is added to the residue, and then concentrated by distillation under reduced pressure. The operation of adding solvent B and then concentrating is repeated 3 times, each time using solvent B toluene The mass dosage is 2 to 5 times of the residue mass to obtain a solid; The solvent A is any one of dichloromethane, toluene, ethyl acetate, and N,N-dimethylformamide, and the mass dosage of the solvent A is 0 to 3 times the mass of quinazolin-4-one ; c. Branching reaction: Dissolve the solid in solvent C, then add alkali, N-bromopropylmorpholine and chlorofluoroaniline in sequence, heat up to 80-100°C and stir for 2-6 hours at the reaction temperature. After completion, cool to room temperature to obtain the reacted material; The solvent C is any one of dichloromethane, toluene, ethyl acetate, N,N-dimethylformamide, butanol, and acetone, and the mass dosage of the solvent C is 20-20% of the solid matter. 50 times; d. Post-treatment: add solvent D to mix with the reacted material under stirring, then stir for 1.5-2.5h, filter, and dry the solid to obtain the crude product of gefitinib; the crude product of gefitinib is recrystallized with solvent E That is, the gefitinib product is obtained; The solvent D is any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent D is 2 to 5 times the mass of the reacted material; The solvent E is any one of water, methanol, ethanol, isopropanol, butanol, ethyl acetate, and acetone, and the mass dosage of the solvent E is 10 to 30 times that of the crude product of gefitinib. 3. according to the preparation method of the described gefitinib of claim 1 or 2, it is characterized in that: described water is distilled water or deionized water.