阅读说明：本技术 一种抑制肿瘤细胞药物的合成方法 (Synthesis method of medicine for inhibiting tumor cells ) 是由 王爱平 于 2019-11-28 设计创作，主要内容包括：本发明涉及有机合成和药物技术领域,保护了一种抑制肿瘤细胞药物的合成方法。该合成方法以3-羟基-4-甲氧基苯甲醛为起始原料,先通过临时导向基团活化醛基邻位氢,方便氨基取代,结合[4+2]环合加成反应关环,依次在羟基上引入丙基吗啉侧链,氯化,引入氟氯苯胺侧链,最后制得吉非替尼。该合成方法改进了抑制肿瘤细胞药物吉非替尼的合成路径,减少了反应步骤,缩短了反应时间,降低了生产成本,同时也降低了体系中杂质的生成,减少了三废的排放。(The invention relates to the technical field of organic synthesis and medicines, and protects a synthesis method of a medicine for inhibiting tumor cells. The synthesis method comprises the steps of taking 3-hydroxy-4-methoxybenzaldehyde as an initial raw material, activating aldehyde group ortho-hydrogen through a temporary guide group to facilitate amino substitution, combining [4+2] cycloaddition reaction to close a ring, sequentially introducing a propyl morpholine side chain to a hydroxyl group, chlorinating, introducing a fluorochloroaniline side chain, and finally preparing gefitinib. The synthesis method improves the synthesis route of the tumor cell inhibiting medicament gefitinib, reduces reaction steps, shortens reaction time, reduces production cost, reduces the generation of impurities in a system and reduces the discharge of three wastes.)

1. A method for synthesizing a tumor cell inhibiting drug is characterized by comprising the following steps:

the first step is as follows: synthesis of 2-amino-5-hydroxy-4-methoxybenzaldehyde (B)

Adding 3-hydroxy-4-methoxybenzaldehyde (A), ammonia water, bis (trifluoromethanesulfonyl) silver imide, silver trifluoroacetate, trifluoroacetic acid and ligand amine into 1, 2-dichloroethane, heating for a period of time by adopting a one-pot method, adding water and dichloromethane into a reaction liquid for extraction after TLC (thin layer chromatography) monitoring reaction is completed, collecting organic layers, combining the obtained organic layers, and concentrating under reduced pressure until no liquid is distilled off to obtain a light brown solid, namely a compound B;

the specific reaction formula is as follows:

the second step is that: synthesis of 6-hydroxy-7-methoxyquinazolin-4 (3H) one (C)

Dissolving 2-amino-5-hydroxy-4-methoxybenzaldehyde (B) in N, N-dimethylformamide, sequentially adding formamide and cesium carbonate, stirring at room temperature, performing TLC (thin layer chromatography) monitoring reaction to obtain a reaction solution, performing reduced pressure distillation to obtain a black paste, adding ethyl acetate, heating to dissolve, cooling to crystallize, performing suction filtration after a period of time, and drying a filter cake to obtain a compound C;

the specific reaction formula is as follows:

the third step: synthesis of 7-methoxy-6- (2-morpholinoethoxy) quinazolin-4 (3H) one (D)

Adding 6-hydroxy-7-methoxy quinazoline-4 (3H) ketone (C) into methanol while stirring, then adding N- (3-chloropropyl) morpholine and sodium hydroxide, heating after adding, stirring and refluxing; after the reaction is finished, cooling, filtering, washing a filter cake by using methanol, mixing the filtrate, carrying out reduced pressure distillation to recover the methanol, and obtaining a yellow solid after the methanol is completely distilled; adding ethanol, heating, stirring, refluxing, cooling, crystallizing, filtering, and drying the filter cake to obtain white solid, i.e. compound D;

the specific reaction formula is as follows:

the fourth step: synthesis of 7-methoxy-6- [ 3-morpholinopropoxy ] -4-chloroquinazoline (E)

Adding 7-methoxy-6- (2-morpholinoethoxy) quinazoline-4 (3H) ketone (D) into chloroform, controlling the temperature in an ice-water bath, dropwise adding thionyl chloride into the reaction liquid, controlling the temperature, slowly heating to reflux after the addition is finished, stopping the reaction after a period of time, and cooling to room temperature; removing thionyl chloride under reduced pressure to obtain a dark yellow viscous solid, namely a compound E;

the specific reaction formula is as follows:

the fifth step: synthesis of gefitinib (F)

Adding 7-methoxy-6- [ 3-morpholinopropoxy ] -4-chloroquinazoline (E) into isopropanol, dissolving 3-chloro-4-fluoro-aniline in the isopropanol, dropwise adding the solution into the reaction solution, and stirring at room temperature; after the reaction is finished, adding potassium hydroxide into the reaction solution, stirring at room temperature, performing suction filtration, washing a filter cake with a proper amount of isopropanol and ethanol in sequence, and performing vacuum drying to obtain a light beige powdery solid, namely gefitinib (F);

the specific reaction formula is as follows:

2. the method for synthesizing a drug for suppressing tumor cells according to claim 1, wherein the ligand amine used in the first step is m-bistrifluoromethylaniline.

3. The method for synthesizing a drug for suppressing tumor cells according to claim 1 or 2, wherein in the first step, the aldehyde group is combined with a ligand amine to form a temporary directing group imine so that the hydrogen in the ortho position of the aldehyde group is easily substituted.

4. The method for synthesizing a drug for inhibiting tumor cells according to claim 1, wherein in the third step, the compound C is reacted with N- (3-chloropropyl) morpholine at a reaction temperature of 80-85 ℃.

5. The method for synthesizing a drug for inhibiting tumor cells according to claim 1 or 4, wherein in the third step, the compound D is purified by dissolving in ethanol at an elevated temperature and then crystallizing at a cooling temperature, and the crystallization temperature at which the yield is the highest is-10 ℃.

6. The method for synthesizing a drug for inhibiting tumor cells according to claim 1, wherein in the fourth step, the heat is released in the process of adding thionyl chloride dropwise into the reaction solution, and an ice-water bath is required to control the temperature to be-5-0 ℃.

7. The method for synthesizing a drug for inhibiting tumor cells according to claim 1 or 6, wherein in the fourth step, the reaction temperature of compound D with thionyl chloride is 95 ℃.

8. The compound gefitinib obtained by the method for synthesizing the tumor cell inhibiting drug according to any one of claims 1 to 7.

9. Gefitinib, obtainable according to claim 8, for use in combination with afatinib in the treatment of EGFR mutation positive non-small cell lung cancer.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of a tumor cell inhibiting drug.

Background

Gefitinib, also known as iressa, chemical name: n- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholin-4-propoxy) quinazolin-4-amine; the molecular formula is as follows: c ₂₂H ₂₄ClFN ₄O ₃(ii) a Molecular weight: 447 (c); CAS number: 184475-35-2; english chemical name: n- (3-chloro-4-fluoro-phenyl) -7-methoxy-6- (3-morpholino-4-ylpropoxy) quinazolin-4-amine.

Chemical structural formula:

gefitinib, a quinazoline derivative, is a selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor and can be used for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer that has undergone chemotherapy or is otherwise unable to undergo chemotherapy.

There are several methods for the synthesis of gefitinib. Patent WO9633980, 6, 7-dimethoxyquinazolin-4- (3H) -ketone (1) is used as a starting material, methanesulfonic acid and L-methionine are used for selective demethylation to obtain 6-hydroxy-7-methoxyquinazolin-4- (3H) -ketone (2), acetylation reaction is carried out to obtain (3), chlorination is carried out to obtain (4), 3-chloro-4-fluoroaniline is aminated to obtain (5), and deacetylation reaction is carried out to obtain (6), a large amount of methanesulfonic acid and L-methionine are used in the line, the two reagents can not be recycled, a column chromatography is also needed to separate a final product in the reaction process, the synthesis line is long, the environmental pollution is large, the operation is complex, the total yield is low, and the method is not suitable for industrial production. Patent WO2004024703 (astrazeneca) uses 3-hydroxy-4-methoxybenzaldehyde (1) as a starting material to prepare 3-hydroxy-4-methoxybenzonitrile, which is then etherified, nitrated, reduced, hydrolyzed, cyclized and chlorinated, and finally aminated with 3-chloro-4-fluoroaniline to obtain gefitinib. Although the improved process avoids the step of selective demethylation, the chlorination reaction easily generates byproducts, the hydrolysis of cyano groups is difficult to control, and the improved process cannot avoid the byproducts of acid and is not suitable for large-scale industrial production.

Disclosure of Invention

Aiming at the problems of the prior art, the invention discloses a synthesis method of a tumor cell inhibiting medicament gefitinib. The technical scheme of the invention is as follows:

a method for synthesizing a medicament gefitinib for inhibiting tumor cells comprises the following steps:

the first step is as follows: synthesis of 2-amino-5-hydroxy-4-methoxybenzaldehyde (B)

Adding 3-hydroxy-4-methoxybenzaldehyde (A), ammonia water, bis (trifluoromethanesulfonyl) silver imide, silver trifluoroacetate, trifluoroacetic acid and ligand amine into 1, 2-dichloroethane, heating to 50 ℃ by adopting a one-pot method, and heating for reacting for 24 hours. After TLC monitoring reaction is completed, adding water and dichloromethane into the reaction solution for extraction, collecting organic layers, and combining the obtained organic layers; concentrating under reduced pressure until no liquid is distilled off to obtain light brown solid, namely compound B.

The specific reaction formula is as follows:

the second step is that: synthesis of 6-hydroxy-7-methoxyquinazolin-4 (3H) one (C)

2-amino-5-hydroxy-4-methoxybenzaldehyde (B) was dissolved in N, N-dimethylformamide, and formamide and cesium carbonate were added in this order and stirred at room temperature for 2 hours. And after TLC monitoring reaction is completed, carrying out reduced pressure distillation on the reaction solution to obtain black paste, adding ethyl acetate, heating to dissolve, cooling to crystallize, carrying out suction filtration after a period of time, and drying a filter cake to obtain a compound C.

The specific reaction formula is as follows:

the third step: synthesis of 7-methoxy-6- (2-morpholinoethoxy) quinazolin-4 (3H) one (D)

Adding 6-hydroxy-7-methoxy quinazoline-4 (3H) ketone (C) into methanol while stirring, then adding N- (3-chloropropyl) morpholine and sodium hydroxide, heating after the addition, stirring and refluxing for 5H. After the reaction is finished, cooling to room temperature, carrying out suction filtration on the reaction solution, washing a filter cake with methanol, mixing the filtrates, carrying out reduced pressure distillation to recover the methanol, and completely distilling to obtain a yellow solid. Adding ethanol, heating to 45 ℃, stirring and refluxing for 2-3 h, cooling and crystallizing, carrying out suction filtration, and drying a filter cake to obtain a white solid, namely a compound D.

The specific reaction formula is as follows:

the fourth step: synthesis of 7-methoxy-6- [ 3-morpholinopropoxy ] -4-chloroquinazoline (E)

Adding 7-methoxy-6- (2-morpholinoethoxy) quinazoline-4 (3H) ketone (D) into chloroform, controlling the temperature in an ice-water bath, dropwise adding thionyl chloride into the reaction liquid, controlling the temperature, stirring for 30min at 0 ℃, slowly heating to reflux, after 4H of reaction, carrying out HPLC tracking detection, and cooling the reaction liquid to room temperature after the raw materials completely react. The thionyl chloride was removed under reduced pressure to give a dark yellow viscous solid, compound E.

The specific reaction formula is as follows:

the fifth step: synthesis of gefitinib (F)

Adding 7-methoxy-6- [ 3-morpholinopropoxy ] -4-chloroquinazoline (E) into isopropanol, dissolving 3-chloro-4-fluoro-aniline in the isopropanol, dropwise adding the solution into the reaction solution, and stirring at room temperature. And after the reaction is finished, adding potassium hydroxide into the reaction solution, stirring at room temperature, performing suction filtration, washing a filter cake with a proper amount of isopropanol and ethanol in sequence, and performing vacuum drying at 55 ℃ to constant weight to obtain light beige powdery solid, namely the gefitinib.

The specific reaction formula is as follows:

preferably, in the first step, the ligand amine used is m-ditrifluoromethylaniline.

Preferably, in the first step, the aldehyde group is bonded to the amine ligand to form a temporary directing group imine, so that the hydrogen ortho to the aldehyde group is easily substituted.

Preferably, in the third step, the reaction of the compound C and N- (3-chloropropyl) morpholine needs to be carried out at a reaction temperature of 80-85 ℃.

Preferably, in the third step, the compound D is purified by dissolving the compound D in ethanol at an elevated temperature. And cooling for crystallization, wherein the crystallization temperature with the maximum yield is-10 ℃.

Preferably, in the fourth step, heat is released in the process of adding thionyl chloride dropwise into the reaction solution, and the temperature of the ice water bath is controlled to be-5-0 ℃.

Preferably, in the fourth step, the reaction temperature of the compound D with thionyl chloride is 95 ℃.

Preferably, the gefitinib compound is obtained by the synthesis method of the tumor cell inhibiting drug.

Preferably, the gefitinib obtained in the above step is used for treating EGFR mutation-positive non-small cell lung cancer by acting together with afatinib.

The invention has the beneficial effects that:

the method still uses 3-hydroxy-4-methoxybenzaldehyde as a starting material, firstly replaces the ortho position of aldehyde group with amino, closes the ring through [4+2] cycloaddition reaction, then introduces propyl morpholine side chain on the hydroxy, chloridizes, introduces fluorine chloroaniline side chain, and finally prepares gefitinib. Compared with the prior art, the method simplifies the reaction steps, shortens the reaction period, reduces the cost and lightens the pollution to the environment.

Detailed Description

The invention is described in detail below with reference to specific embodiments:

the synthetic route of the invention is as follows: