CN109384664B - Preparation method of erlotinib intermediate - Google Patents
Preparation method of erlotinib intermediate Download PDFInfo
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Abstract
The invention discloses a preparation method of an erlotinib intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid, which optimizes a preparation route method, optimizes reaction conditions, improves post-treatment and purification methods, and reduces operation risk level and production cost; the requirement on the corrosion resistance level of reaction container equipment is low, the operation safety is good, the post-treatment is green and environment-friendly, the obtained 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid intermediate has low impurity content, the purity and the quality of an intermediate product are greatly improved while the yield is improved, the difficulty of process control in the production process of the active pharmaceutical ingredient of the alendronic acid is improved, and the quality and the qualification rate of the active pharmaceutical ingredient of the alendronic acid are improved; the preparation method has the advantages of simple operation of each step, safe and feasible solvent and process conditions, realization of environment-friendly and green production and wide application prospect.
Description
Technical Field
The invention relates to the technical field of synthesis of drug intermediates, and in particular relates to a preparation method of an erlotinib intermediate.
Background
The novel anticancer drug Alectinib is an inhibitor of novel Anaplastic Lymphoma Kinase (ALK), is used for treating advanced or metastatic ALK positive non-small cell lung cancer, and is suitable for patients who do not tolerate crizotinib and are worsened after treatment.
A key intermediate for synthesizing the Aleptinib, namely 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid, has a molecular formula as follows: c12H15IO2And English names are: 2- (4-Ethyl-3-iodophenyl) -2-methylpropanoic acid, the structural formula of which is shown as the following formula:
in the prior art, a preparation method of 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid is disclosed, and WO2004/046080 document takes 2- (4-bromophenyl) -2-methylpropanoic acid as a starting material, introduces ethyl at the position of benzene ring bromine through two-step reactions of Suzuki coupling catalyzed by palladium acetate and hydrogenation reduction of double bond catalyzed by palladium carbon, and finally obtains an intermediate product 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid through iodination, wherein the preparation method route is shown as follows;
the raw materials and reagents of the preparation method, namely 2- (4-bromophenyl) -2-methylpropanoic acid, potassium vinyltrifluoroborate and palladium acetate ethyl palladium carbon, are high in price, the operation conditions need to be strictly controlled to be anaerobic, the operation difficulty is increased, heavy metal palladium in the prepared 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid product is easy to remain, and the preparation method is not beneficial to scale-up production and industrial popularization; in addition, the residual heavy metal palladium in the intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid product is easy to cause the key intermediate of the alendronic acid in the storage process, the purity of the 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid is reduced, and when the alendronic acid product is synthesized subsequently, the residual heavy metal palladium is brought into the alendronic acid product, so that the purification is difficult, and the quality improvement of the alendronic acid product is not facilitated.
CN106946650A literature uses 2-bromo-2-methylpropanoic acid as starting material to obtain an intermediate product 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid through 5 steps of chlorination, Friedel-crafts acylation reaction, rearrangement reaction, iodination and hydrolysis reaction, and the preparation method route is shown as follows;
the preparation method has long route, uses a large amount of hazardous reagents of thionyl chloride and aluminum trichloride in the process, has corrosion hazard to reaction container equipment, generates a large amount of corrosive sewage in post-treatment, and is not beneficial to green and environment-friendly industrial production.
In summary, the preparation method of the ailtinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid product disclosed in the prior art has the disadvantages of long preparation route, expensive raw materials and reagents, high preparation cost, heavy metal residue in the target product, poor product quality, and generation of a large amount of acid gas and wastewater in the post-treatment stage, so that green and environment-friendly industrial production cannot be realized, or the raw materials and the reagents are hazardous reagents, so that the operation safety is poor, the production safety level and the production cost are improved, and the industrial popularization and application are not facilitated.
Therefore, there is a need for developing and optimizing a preparation method of an neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, particularly a preparation method capable of performing workshop amplification and meeting the requirements of environmental protection.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide the preparation method of the 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, which is an intermediate of the Aleptinib, and has the advantages of short flow, simple operation, low cost, environmental friendliness and suitability for industrial production.
One aspect of the invention provides a preparation method of an erlotinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (formula A),
the preparation method comprises the following steps:
step 1, performing coupling reaction on a compound A-1 and a compound A-2 in the presence of a catalyst and alkali, and hydrolyzing to obtain a compound A-3;
step 2, reacting the compound A-3 with R in the presence of an acid catalyst2Performing esterification reaction on OH to obtain a compound A-4;
step 3, carrying out double methylation reaction on the compound A-4 and a methylating agent in the presence of alkali, and hydrolyzing to obtain a compound A-5;
and 4, performing iodination reaction on the compound A-5 to obtain an Alletinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (formula A).
The preparation route is as follows:
wherein R is1Is C1-C10 alkyl; r2Is C1-C10 alkyl or arylalkyl.
Further, said R1Is methyl, ethyl or tert-butyl;
further, said R2Is methyl, ethyl, tert-butyl or benzyl;
further, in the step 1, the catalyst is cuprous halide; the base is a metal base;
further, in the step 1, the catalyst is one or more of cuprous iodide, cuprous bromide and cuprous chloride; the alkali is one or more of sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide and sodium tert-butoxide;
further, in the step 1, the molar ratio of the compound A-1 to the compound A-2 is 1: 1.5-1: 2.5;
further, in the step 1, the molar ratio of the compound A-1 to the catalyst is 1: 0.2-1: 0.6;
further, in the step 1, the molar ratio of the compound A-1 to the alkali is 1: 1.5-1: 2.5;
further, in the step 1, a reaction solvent of the coupling reaction is an ether solvent;
further, the ether solvent is one or more of ethylene glycol dimethyl ether, 1, 4-dioxane or tetrahydrofuran;
further, in the step 1, the reaction temperature of the coupling reaction is 60-80 ℃, and the reaction time is 10-14 hours;
further, the step 1 specifically comprises: reacting the compounds A-1 and A-2 for 10-14 hours at the reaction temperature of 60-80 ℃ by taking an ether solvent as a solvent in the presence of a metal alkali and cuprous halide as a catalyst, hydrolyzing, and performing post-treatment to obtain a compound A-3;
wherein, the mol ratio of the compound A-1 to the compound A-2 to the cuprous halide to the metal alkali is 1 (1.5-2.5) to (0.2-0.6) to (1.5-2.5);
further, in the step 2, the acidic catalyst is one or more of concentrated sulfuric acid, acetyl chloride and thionyl chloride;
further, in the step 2, the R2OH is one of methanol, ethanol, tert-butyl alcohol and benzyl alcohol;
further, in the step 2, the molar ratio of the compound A-3 to the acidic catalyst is 1: 0.05-1: 0.3;
further, in the step 2, the compounds A-3 and R2The weight-to-volume ratio (g/mL) of OH is 1: 1-1: 10;
further, in the step 2, the reaction temperature of the esterification is 40-65 ℃, and the reaction time is 4-5 hours;
further, the step 2 specifically includes: the compound A-3 reacts with R in the presence of an acidic catalyst2Reacting OH at 40-65 ℃ for 4-5 hours, and performing post-treatment to obtain a compound A-4;
wherein the molar ratio of the compound A-3 to the acidic catalyst is 1: 0.05-1: 0.3; compounds A-3 and R2The weight-to-volume ratio (g/mL) of OH is 1: 1-1: 10;
further, in the step 3, the methylating agent is methyl iodide; the base is a metal base;
further, the metal base is one or more of sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide and sodium tert-butoxide;
further, in the step 3, the reaction solvent of the double methylation reaction is an aprotic solvent;
further, the aprotic solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide and 1, 4-dioxane;
further, in the step 3, the molar ratio of the compound A-4 to the methylating agent is 1: 2-1: 4;
further, in the step 3, the molar ratio of the compound A-4 to the metal base is 1: 2-1: 4;
further, in the step 3, the weight-to-volume ratio (g/mL) of the compound A-4 to the aprotic solvent is 1:5 to 1: 15;
further, in the step 3, the reaction temperature of the double methylation reaction is-10 to 25 ℃, and the reaction time is 5 to 7 hours;
further, the step 3 specifically includes: reacting the compound A-4 with a methylating agent in the presence of metal alkali at-10-25 ℃ for 5-7 hours by using an aprotic solvent as a solvent, hydrolyzing and carrying out post-treatment to obtain a compound A-5;
wherein the molar ratio of the compound A-4, the methylating agent and the metal base is 1 (2-4) to 2-4; the weight-to-volume ratio (g/mL) of the compound A-4 to the aprotic solvent is 1:5 to 1: 15;
further, in the step 4, the iodination reagent for the iodination reaction is one or more of N-iodosuccinimide and iodine simple substance;
further, in the step 4, the catalyst for the iodination reaction is concentrated sulfuric acid;
further, in the step 4, the reaction solvent for the iodination reaction is one or more of glacial acetic acid, dichloromethane, ethyl acetate and tetrahydrofuran;
further, in the step 4, the molar ratio of the compound A-5 to the iodinating reagent is 1 (1.1-1.5);
further, in the step 4, the weight-to-volume ratio (g/mL) of the compound A-5 to the solvent is 1 (3-5);
further, in the step 4, the weight-to-volume (g/mL) ratio of the compound A-5 to the catalyst is 1 (1-2);
further, in the step 4, the reaction temperature of the iodination reaction is 20-30 ℃, and the reaction time is 2-4 hours;
further, the step 4 specifically includes: reacting the compound A-5 for 2-4 hours at 20-30 ℃ in the presence of an iodinated reagent, a catalyst and a reaction solvent, and performing aftertreatment to obtain an neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (formula A);
wherein the molar ratio of the compound A-5 to the iodinating reagent is 1 (1.1-1.5); the weight-to-volume ratio (g/mL) of the compound A-5 to the solvent is 1 (3-5); the weight-to-volume ratio (g/mL) of the compound A-5 to the catalyst is 1 (1-2).
According to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of elotinib, in step 1, the catalyst is cuprous iodide;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of elotinib, in step 1, the catalyst is cuprous bromide;
according to a preferred embodiment of the method for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, which is an intermediate of idetinib, in the step 1, the catalyst is a mixed catalyst of cuprous iodide and cuprous bromide;
according to a preferred embodiment of the preparation method of the neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, in the step 1, the molar ratio of cuprous iodide to cuprous bromide in the mixed catalyst is 1: 1-1: 3;
according to a preferred embodiment of the process for the preparation of the intermediate of neratinib, 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, according to the present invention, in step 1, the base is sodium methoxide;
according to a preferred embodiment of the process for the preparation of the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid of the present invention, in step 1, the base is sodium hydride;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of alendronic acid, the base is potassium tert-butoxide in the step 1;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of alentinib, in step 1, the molar ratio of compound a-1 to a-2 is 1: 1.5;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of alentinib, in step 1, the molar ratio of compound a-1 to a-2 is 1: 2;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of alentinib, in step 1, the molar ratio of compound a-1 to a-2 is 1: 2.5;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of elotinib, in step 1, the molar ratio of compound a-1 to the catalyst is 1: 0.2;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of elotinib, in step 1, the molar ratio of compound a-1 to the catalyst is 1: 0.4;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of elotinib, in step 1, the molar ratio of compound a-1 to the catalyst is 1: 0.6;
according to a preferred embodiment of the process for the preparation of the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid of the present invention, in said step 1, the molar ratio of compound a-1 to base is 1: 1.5;
according to a preferred embodiment of the process for the preparation of the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid of the present invention, in said step 1, the molar ratio of compound a-1 to base is 1: 2;
according to a preferred embodiment of the process for the preparation of the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid of the present invention, in said step 1, the molar ratio of compound a-1 to base is 1: 2.5;
according to a preferred embodiment of the preparation method of the neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, in the step 1, the molar ratio of the compounds A-1 and A-2, the catalyst and the base is 1:2:0.4: 2;
according to a preferred embodiment of the method for preparing the neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, in the step 1, the molar ratio of cuprous iodide to cuprous bromide in the mixed catalyst is 1: 1;
according to a preferred embodiment of the method for preparing the neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, in the step 1, the molar ratio of cuprous iodide to cuprous bromide in the mixed catalyst is 1: 2;
according to a preferred embodiment of the method for preparing the neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, in the step 1, the molar ratio of cuprous iodide to cuprous bromide in the mixed catalyst is 1: 3;
according to a preferred embodiment of the process for preparing an neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid according to the present invention, in the step 2, the molar ratio of the compound a-3 to the acidic catalyst is 1: 0.05;
according to a preferred embodiment of the process for preparing an neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid according to the present invention, in the step 2, the molar ratio of the compound a-3 to the acidic catalyst is 1: 0.1;
according to a preferred embodiment of the process for preparing an neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid according to the present invention, in the step 2, the molar ratio of the compound a-3 to the acidic catalyst is 1: 0.3;
according to a preferred embodiment of the process for the preparation of the Alletinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid of the present invention, in said step 2, the compounds A-3 and R2The weight-to-volume ratio (g/mL) of OH is 1: 1;
according to a preferred embodiment of the process for the preparation of the Alletinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid of the present invention, in said step 2, the compounds A-3 and R2The weight-to-volume ratio (g/mL) of OH is 1: 5;
according to a preferred embodiment of the process for the preparation of the Alletinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid of the present invention, in said step 2, the compounds A-3 and R2The weight-to-volume ratio (g/mL) of OH is 1: 10;
according to a preferred embodiment of the process for the preparation of the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid of the present invention, in said step 3, the molar ratio of compound a-4 to methylating agent is 1: 2;
according to a preferred embodiment of the process for the preparation of the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid of the present invention, in said step 3, the molar ratio of compound a-4 to methylating agent is 1: 3;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of Alletinib, said step 3, the molar ratio of compound A-4 to methylating agent is 1:4
According to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of alentinib, in said step 3, the molar ratio of compound a-4 to the metal base is 1: 2;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of alentinib, in said step 3, the molar ratio of compound a-4 to the metal base is 1: 3;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of alentinib, in said step 3, the molar ratio of compound a-4 to the metal base is 1: 4;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of alentinib, in said step 3, the weight to volume ratio (g/mL) of compound a-4 to the aprotic solvent is 1: 5;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of alendronic acid, in step 3, the weight to volume ratio (g/mL) of compound a-4 to the aprotic solvent is 1: 10;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of alentinib, in said step 3, the weight to volume ratio (g/mL) of compound a-4 to the aprotic solvent is 1: 15;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of alentinib, in step 3, the molar ratio of the compound a-4, methyl iodide and the metal base is 1:3: 3;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of alentinib, in step 4, the molar ratio of compound a-5 to the iodo reagent is 1: 1.1;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of alentinib, in step 4, the molar ratio of compound a-5 to the iodo reagent is 1: 1.2;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid, an intermediate of alentinib, in step 4, the molar ratio of compound a-5 to the iodo reagent is 1: 1.5;
according to a preferred embodiment of the method for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of alentinib, in step 4, the weight to volume ratio (g/mL) of the compound a-5 to the solvent is 1: 3;
according to a preferred embodiment of the method for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of alentinib, in step 4, the weight to volume ratio (g/mL) of the compound a-5 to the solvent is 1: 4;
according to a preferred embodiment of the method for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of alentinib, in step 4, the weight to volume ratio (g/mL) of the compound a-5 to the solvent is 1: 5;
according to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an intermediate of alendronic acid, in the step 4, the weight to volume ratio (g/mL) of the compound a-5 to the catalyst is 1: 1.0;
according to a preferred embodiment of the method for preparing the Aleptinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, in the step 4, the weight-to-volume ratio (g/mL) of the compound A-5 to the catalyst is 1:1.5
According to a preferred embodiment of the process for preparing 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid, an exenatide intermediate, in the step 4, the weight to volume ratio (g/mL) of the compound a-5 to the catalyst is 1: 2.0.
The technical parameter characteristics in the above preparation method of the present invention can be combined at will.
In the above operations, the post-treatment includes, but is not limited to, stirring, liquid or solid transferring, water washing, alkali washing, acid washing, PH adjusting, filtering, ultrafiltration, circulating ultrafiltration, suction filtration, dilution, concentration, drying, recrystallization, freeze-drying, or the like, or one or more of stirring, liquid or solid transferring, water washing, alkali washing, acid washing, PH adjusting, filtering, ultrafiltration, circulating ultrafiltration, suction filtration, dilution, concentration, drying, recrystallization, freeze-drying, and the like.
In the field of synthesis of organic compound molecules as pharmaceutical intermediates, the purity of the intermediate compound and the maximum single impurity content thereof greatly affect the quality of the final pharmaceutical product. The chemical synthesis reaction has the characteristics that reaction sites are not single, and the reaction of impurities is carried out simultaneously and is inevitable. Generally, it is very difficult to improve the purity of a pharmaceutical product compound to a higher level on the basis of reaching a certain purity by optimizing a synthesis method and optimizing reaction conditions. On the other hand, in order to reduce the toxic and side effects that may be caused by impurities in pharmaceutical products, pharmaceutical products have extremely high requirements in terms of purity and content, as living individuals to be administered to humans or other animals for the treatment of diseases. Therefore, the method can meet the requirement of industrial scale-up production, improve the purity of the medical product, reduce the maximum single impurity content, improve the production and preparation methods of different medical products on the basis of not reducing the yield, and has no regular cycle or ready experience and inspiration for reference.
Specifically, according to the invention, the purity and quality of the neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid have a large influence on the quality of the final product neratinib, and the influence of the purity on the purity of the final product neratinib is further amplified in the subsequent preparation process. Therefore, the compound 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (formula A) as a key intermediate of the neratinib, must be subjected to more stringent quality control.
Compared with the prior art, the preparation method of the neratinib intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid has the following beneficial effects:
the preparation method of the Aleptinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid optimizes and improves the preparation route method, does not use expensive raw materials and metal palladium catalysts, greatly reduces the preparation cost, has mild operation conditions, does not need to control anaerobic conditions, reduces the operation difficulty, and is favorable for large-scale production and industrial popularization; the residue of heavy metal palladium in the Alexanib intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid is avoided, the quality of the intermediate compound is improved, and reliable guarantee is provided for the quality of the subsequent preparation of the Alexanib product;
the preparation method of the Aleptinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid optimizes and improves the preparation route method, does not use dangerous reagents such as thionyl chloride and aluminum trichloride, has low requirement on the corrosion resistance level of container equipment for reaction, has good operation safety, reduces the potential threat level to the life hazard of staff at the production line, has green and environment-friendly post-treatment, does not generate a large amount of corrosive sewage, reduces the safety level and the production cost of production, and is beneficial to the application of green and environment-friendly industrial production;
the preparation method of the Aleptinib intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid optimizes and improves the preparation route method, the post-treatment of the reaction in each step is conventional treatment, column chromatography and other purification operations are not used, the operation is simple and convenient, the reaction yield in each step is high, the side reaction is less, the raw materials required by the reaction are cheap and easy to obtain, the reaction condition is mild, and the method is suitable for industrial production;
the 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid product prepared by the preparation method of the neratinib intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid has few impurities, particularly the maximum single impurity content is less than 0.1 percent, so that the purity and the quality of the intermediate product are greatly improved; the preparation method is used for producing the alendronate by taking the alendronate intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid obtained by the preparation method as a key intermediate, so that the purity and the quality of the alendronate are improved, and the toxic and side effects of the alendronate as a medicine are reduced;
the purity of the Aleptinib intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid prepared by the preparation method is improved to more than 99.5%, the maximum single impurity content is below 0.1%, the intermediate in each step is easy to purify, and the post-treatment is simple, convenient and easy to operate;
the preparation method disclosed by the invention has the advantages that the stability of the Alexanib intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid is good, the purity of the Alexanib intermediate is not obviously changed when the Alexanib intermediate is placed under severe conditions, the storage and the transportation are convenient, the introduction of various impurities during the reaction of the Alexanib intermediate is greatly reduced, the quality and the purity of the prepared Alexanib medicine are favorably improved, the medication toxicity of the Alexanib is reduced, and the medication safety is improved.
In conclusion, the preparation method for preparing the Aleptinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid optimizes and improves the preparation route method, does not use expensive raw materials and metal palladium catalysts, and does not use dangerous reagents such as thionyl chloride and aluminum trichloride; the operation danger level and the production cost are reduced; the requirement on the corrosion resistance level of reaction container equipment is low, the operation safety is good, the post-treatment is green and environment-friendly, the obtained 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid intermediate has low impurity content, the yield is improved, and the purity and quality of the intermediate product are greatly improved, so that the difficulty of process control in the production process of the active pharmaceutical ingredient of the alendronate is improved, and the quality and the qualification rate of the active pharmaceutical ingredient of the alendronate are improved; the method has the advantages of simple and easy steps, safe and cheap solvent and process conditions, environmental-friendly and green industrial production realization, and wide application prospect.
Detailed Description
All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations of features and/or steps that are mutually exclusive.
Any feature disclosed in this specification may be replaced by alternative features serving equivalent or similar purposes, unless expressly stated otherwise. That is, unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features.
The process for preparing the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid of the present invention will be described in further detail below.
According to an exemplary embodiment of the present invention, the preparation method of the neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid comprises the following steps:
the compound A-2 is mixed with metal alkali and ether solvent, cuprous halide and the compound A-1 are added after the temperature of reaction liquid is raised, and the molar ratio of the compound A-1 to the compound A-2 to the cuprous halide to the metal alkali is 1:2:0.4: 2; reacting the reaction solution at 60-80 ℃ for 10-14 hours; sequentially carrying out alkali treatment, acid treatment, suction filtration, water washing, drying and recrystallization to obtain a compound A-3;
compounds A-3, R2OH and an acid catalyst are mixed, and the molar ratio of the compound A-3 to the acid catalyst is 1: 0.1; compounds A-3 and R2The weight-to-volume ratio (g/mL) of OH is 1: 5; heating the reaction solution to 40-65 ℃ for reaction for 4-5 hours; concentrating, washing with water, washing with alkali, concentrating and drying to obtain a compound A-4;
mixing and feeding a compound A-4, a methylating agent, a metal base and an aprotic solvent as solvents, wherein the molar ratio of the compound A-4 to the methylating agent to the metal base is 1:3: 3; the weight-to-volume ratio (g/mL) of the compound A-4 to the aprotic solvent is 1: 10; reacting the reaction solution at-10 to 25 ℃ for 5 to 7 hours; alkali treatment, concentration and drying to obtain a compound A-5;
mixing and feeding a compound A-5, an iodinated reagent, a catalyst and a reaction solvent, wherein the molar ratio of the compound A-5 to the iodinated reagent is 1: 1.1; the weight-to-volume ratio (g/mL) of the compound A-5 to the solvent is 1: 3; the weight-to-volume ratio (g/mL) of the compound A-5 to the catalyst is 1: 1.5; heating the reaction solution to 20-30 ℃ for reaction for 2-4 hours; washing, filtering and drying to obtain the intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid (formula A) of the Alletinib.
The purity of the 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (formula a) as an intermediate of the elotinib prepared by the preparation method of the embodiment is 99.5% or more, and the maximum single impurity content is 0.1% or less.
The largest single impurity is the impurity of the single component with the highest content in the medical product, and in the medical synthesis preparation process method, the largest single impurity is the key quality control index of the medical product.
The preparation of the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropionic acid of the present invention will be further described with reference to the following specific examples.
The preparation route of the embodiment of the invention is as follows:
example 1 preparation of Alletinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid
1) Adding 64.0g diethyl malonate (compound A-2a) and 640mL ethylene glycol dimethyl ether into a reaction bottle, adding 21.6g sodium methoxide, heating to 70-75 ℃ for reaction for 0.5h, adding 7.6g cuprous iodide and 5.8g cuprous bromide, and stirring for 1 h; 37.0g of bromoethylbenzene (compound A-1) was added thereto, and the reaction was maintained at 70-75 ℃ for 10-12 hours. Adding 50% sodium hydroxide water solution, maintaining pH at 12, stirring for 4 hr, filtering, and concentrating under reduced pressure to remove solvent; water and hydrochloric acid were added to adjust pH to 1-2, followed by stirring, suction filtration, washing with water, drying, and recrystallization to give Compound A-3(25.0g, yield 76%).
2) Adding 20.0g of compound A-3, 100mL of methanol and 4mL of concentrated sulfuric acid into a reaction bottle, heating to reflux for reaction for 4-5h, concentrating under reduced pressure to remove methanol, sequentially adding water and ethyl acetate, separating, combining organic layers, washing with saturated sodium bicarbonate, and concentrating under reduced pressure to remove ethyl acetate from the organic layer to obtain compound A-4a (18.2g, yield 93%).
3) Adding 17.8g of compound A-4a and 178mL of DMF into a reaction bottle, cooling to 0-10 ℃, adding 12g of 60 wt% sodium hydride, stirring, adding 42.6g of methyl iodide, heating to 15-25 ℃, and reacting for 5-6 h. Adding water and ethyl acetate in sequence, separating, combining organic layers, decompressing and concentrating to remove solvent ethyl acetate, adding lithium hydroxide aqueous solution and 24mL methanol, stirring at 20-30 ℃ for 10-12h, adding water and ethyl acetate, adjusting pH to 1-2 with hydrochloric acid, separating, concentrating the organic layer, and drying to obtain the compound A-5(15.6g, yield 81%).
4) Adding 12.0g of compound A-5 and 36mL of acetic acid into a reaction bottle, cooling to 0-5 ℃, adding 15.5g N-iodosuccinimide and 18mL of concentrated sulfuric acid, heating to 20-30 ℃ and reacting for 2-3 h. Adding saturated sodium bisulfite water solution and water, stirring for 1h, vacuum filtering, and drying the filter cake to obtain the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (formula A) (17.0g, yield 85%).
Example 2
1) 48.0g of diethyl malonate (compound A-2a) and 640mL of 1, 4-dioxane are added into a reaction bottle, 12g of 60 wt% sodium hydride is added, the temperature is raised to 70-75 ℃ for reaction for 0.5h, 7.6g of cuprous iodide is added, after stirring, 37.0g of bromoethylbenzene (compound A-1) is added, and the reaction is kept at 70-75 ℃ for reaction for 10-12 h. Adding 50% sodium hydroxide water solution, maintaining pH at 12, stirring for 4 hr, filtering, and concentrating under reduced pressure to remove solvent; water and hydrochloric acid were added to the residue to adjust the pH to 1-2, followed by stirring, suction filtration, water washing, drying, and recrystallization to give Compound A-3(24.7g, yield 75%).
2) Adding 20.0g of compound A-3, 20mL of methanol and 3.5mL of concentrated sulfuric acid into a reaction flask, heating to reflux for reaction for 4-5h, concentrating under reduced pressure to remove methanol, sequentially adding water and ethyl acetate, separating, combining organic layers, washing with saturated sodium bicarbonate, and concentrating the organic layer under reduced pressure to obtain compound A-4a (18.0g, yield 92%).
3) 17.8g of Compound A-4a and 89mL of THF were added to the reaction flask. Cooling to 0-10 ℃, adding 11g of sodium methoxide, stirring, adding 28.4g of methyl iodide, heating to 15-25 ℃ and reacting for 5-6 h. Water and ethyl acetate were added in this order, and liquid separation was carried out, and the organic layers were combined and concentrated under reduced pressure to remove the solvent ethyl acetate. Adding lithium hydroxide aqueous solution and methanol into the residue, stirring at 20-30 deg.C for 10-12h, adding water and ethyl acetate, adjusting pH to 1-2 with hydrochloric acid, separating, concentrating the organic layer, and drying to obtain compound A-5(15.0g, yield 80%).
4) Adding 12.0g of compound A-5 and 48mL of acetic acid into a reaction bottle, cooling to 0-5 ℃, adding 15.5g N-iodosuccinimide and 12mL of concentrated sulfuric acid, heating to 20-30 ℃, reacting for 2-3h, adding saturated sodium bisulfite aqueous solution and water, stirring for 1h, performing suction filtration, washing a filter cake, and drying to obtain the Allertinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (formula A) (16.8g, yield 84%).
Example 3
1) Adding 80.0g diethyl malonate (compound A-2a) and 640mL tetrahydrofuran into a reaction bottle, adding 56g potassium tert-butoxide, heating to 65-70 ℃ for reaction for 0.5h, adding 17.2g cuprous bromide, stirring, adding 37.0g bromoethylbenzene (compound A-1), and reacting at 65-70 ℃ for 10-12 h. Then adding 50% sodium hydroxide aqueous solution, keeping pH greater than 12, stirring for 4h, filtering, and concentrating under reduced pressure to remove solvent; to the residue was added water, and the pH was adjusted to 1-2 with hydrochloric acid, followed by stirring, suction filtration, water washing, drying, and recrystallization to give Compound A-3(23.6g, yield 72%).
2) 20.0g of compound A-3, 200mL of methanol and 4mL of acetyl chloride were added to a reaction flask, the mixture was heated to reflux and reacted for 4 to 5 hours, methanol was removed by concentration under reduced pressure, water and ethyl acetate were sequentially added, liquid separation was performed, the organic layer was combined, washed with saturated sodium bicarbonate, and ethyl acetate was removed by concentration under reduced pressure to obtain compound A-4a (17.6g, yield 90%).
3) 17.8g of Compound A-4a and 267mL of DMF were added to the reaction flask. Cooling to 0-10 ℃, adding 16g of 60 wt% sodium hydride, stirring, adding 56.8g of methyl iodide, heating to 15-25 ℃ and reacting for 5-6 h. Water and ethyl acetate were added in this order, liquid separation was performed, the organic layers were combined, the solvent ethyl acetate was removed by concentration under reduced pressure, an aqueous solution of lithium sodium hydroxide and 24mL of methanol were added to the residue, the mixture was stirred at 20 to 30 ℃ for 10 to 12 hours, water and ethyl acetate were added thereto, the pH was adjusted to 1 to 2 with hydrochloric acid, liquid separation was performed, the organic layer was concentrated, and drying was performed to obtain compound a-5(15.2g, yield 81%).
4) Adding 12.0g of compound A-5 and 60mL of acetic acid into a reaction bottle, cooling to 0-5 ℃, adding 21.1g N-iodosuccinimide and 24mL of concentrated sulfuric acid, heating to 20-30 ℃, reacting for 2-3h, adding saturated sodium bisulfite aqueous solution and water, stirring for 1h, performing suction filtration, and drying a filter cake to obtain an Allertinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (formula A) (17.8g, yield 89%).
Example 4
1) Adding 48.0g diethyl malonate (compound A-2a) and 640mL ethylene glycol dimethyl ether into a reaction bottle, adding 27.0g sodium methoxide, heating to 60-65 ℃ for reaction for 0.5h, adding 3.8g cuprous iodide and 8.7g cuprous bromide, and stirring for 1 h; then 37.0g of bromoethylbenzene (compound A-1) is added, and the reaction is kept at 60-65 ℃ for 10-12 h. Then 50% aqueous sodium hydroxide solution was added, the pH was maintained at >12 and stirred for 4h before filtration and concentration under reduced pressure to remove the solvent. Water and hydrochloric acid were added to the residue to adjust the pH to 1-2, followed by stirring, suction filtration, water washing, drying, and recrystallization to give Compound A-3(24.3g, yield 74%).
2) Adding 20.0g of compound A-3, 100mL of methanol and 4mL of thionyl chloride into a reaction flask, heating to reflux for reaction for 4-5h, concentrating under reduced pressure to remove methanol, sequentially adding water and ethyl acetate, separating, combining organic layers, washing with saturated sodium bicarbonate, and concentrating under reduced pressure to remove ethyl acetate from the organic layer to obtain compound A-4a (17.4g, yield 89%).
3) Adding 17.8g of compound A-4a and 178mL of DMF into a reaction bottle, cooling to 0-10 ℃, adding 12g of 60 wt% sodium hydride, stirring, adding 42.6g of methyl iodide, heating to 15-25 ℃, and reacting for 5-6 h. Adding water and ethyl acetate in sequence, separating, combining organic layers, decompressing and concentrating to remove solvent ethyl acetate, adding lithium hydroxide aqueous solution and 24mL methanol into residue, stirring for 10-12h at 20-30 ℃, adding water and ethyl acetate, adjusting pH to 1-2 with hydrochloric acid, separating, concentrating the organic layer, and drying to obtain compound A-5(16.0g, yield 82%).
4) Adding 12.0g of compound A-5 and 36mL of acetic acid into a reaction bottle, cooling to 0-5 ℃, adding 16.9g N-iodosuccinimide and 18mL of concentrated sulfuric acid, heating to 20-30 ℃ and reacting for 2-3 h. Adding saturated sodium bisulfite water solution and water, stirring for 1h, vacuum filtering, and drying the filter cake to obtain the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (formula A) (18.0g, yield 90%).
Example 5
1) Adding 64.0g diethyl malonate (compound A-2a) and 640mL ethylene glycol dimethyl ether into a reaction bottle, adding 21.6g sodium methoxide, heating to 70-75 ℃ for reaction for 0.5h, adding 3.8g cuprous iodide and 5.8g cuprous bromide, and stirring for 1 h; then 37.0g of bromoethylbenzene (compound A-1) is added, and the reaction is kept at 70-75 ℃ for 10-12 h. Then adding 50% sodium hydroxide aqueous solution, keeping pH greater than 12, stirring for 4h, filtering, and concentrating under reduced pressure to remove solvent; water and hydrochloric acid were added to adjust pH to 1-2, followed by stirring, suction filtration, washing with water, drying, and recrystallization to give Compound A-3(24.0g, yield 73%).
2) Adding 20.0g of compound A-3, 100mL of methanol and 4.5mL of concentrated sulfuric acid into a reaction bottle, heating to reflux for reaction for 4-5h, concentrating under reduced pressure to remove methanol, sequentially adding water and ethyl acetate, separating, combining organic layers, washing with saturated sodium bicarbonate, and concentrating under reduced pressure to remove ethyl acetate from the organic layer to obtain compound A-4a (18.0g, yield 92%).
3) 17.8g of Compound A-4a and 178mL of DMF were added to the reaction flask. Cooling to 0-10 ℃, adding 12g of 60 wt% sodium hydride, stirring, adding 42.6g of methyl iodide, heating to 15-25 ℃ and reacting for 5-6 h. Water and ethyl acetate were added in this order, liquid separation was performed, the organic layers were combined, the solvent ethyl acetate was removed by concentration under reduced pressure, an aqueous lithium hydroxide solution and 24mL of methanol were added to the residue, the mixture was stirred at 20 to 30 ℃ for 10 to 12 hours, water and ethyl acetate were added thereto, the pH was adjusted to 1 to 2 with hydrochloric acid, liquid separation was performed, the organic layer was concentrated, and drying was performed to obtain compound a-5(16.6g, yield 82%).
4) Adding 12.0g of compound A-5 and 36mL of acetic acid into a reaction bottle, cooling to 0-5 ℃, adding 15.5g N-iodosuccinimide and 24mL of concentrated sulfuric acid, heating to 20-30 ℃ and reacting for 2-3 h. Adding saturated sodium bisulfite water solution and water, stirring for 1h, vacuum filtering, and drying the filter cake to obtain the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (formula A) (18.2g, yield 86%).
In the case of other similar implementations of the invention,
in the step 1, dimethyl malonate and di-tert-butyl malonate can be used for replacing diethyl malonate (compound A-2 a);
in the step 2, the methanol may be replaced by ethanol, tert-butanol or benzyl alcohol.
Test example 6:
stability of the intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid (compound a) of the exenatide prepared in the above example was measured, and a sample was placed in a sealed state at normal temperature for six months, and appearance and purity were observed by sampling, and the purity of the compound a was 99.5% or more.
Compared with the sample before placement, the compound A sample has no obvious change in appearance after being placed for 6 months, and has no obvious reduction in purity. The preparation method of the invention is proved that the Aleptinib intermediate 2- (4-ethyl-3-iodine) phenyl-2-methylpropanoic acid compound A has good stability and is beneficial to storage and transportation.
The above examples and test examples show that the purity of the 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid compound A, an intermediate of the preparation method of the present invention, is above 99.5%, and the product stability is good. The method has the advantages of simple and convenient operation of each step, easy purification, simple and convenient post-treatment, environmental protection, easy operation, safe and feasible solvent and conditions, contribution to environmental protection, industrial amplification production and wide application prospect.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (9)
1. A preparation method of an erlotinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid is characterized by comprising the following preparation routes and steps:
the Aleptinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid is shown as a formula A:
the preparation route is as follows:
wherein R is1Is C1-C10 alkyl; r2Is C1-C10 alkyl or arylalkyl;
step 1, performing coupling reaction on a compound A-1 and a compound A-2 in the presence of a catalyst and alkali, and hydrolyzing to obtain a compound A-3;
step 2, reacting the compound A-3 with R in the presence of an acid catalyst2Performing esterification reaction on OH to obtain a compound A-4;
step 3, carrying out double methylation reaction on the compound A-4 and a methylating agent in the presence of alkali, and hydrolyzing to obtain a compound A-5;
and 4, performing iodination reaction on the compound A-5 to obtain an Alletinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid.
2. The method according to claim 1, wherein, in the step 1,
the catalyst is cuprous halide;
the base is a metal base;
the metal alkali is one or more of sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide and sodium tert-butoxide;
the molar ratio of the compound A-1 to the compound A-2 is 1: 1.5-1: 2.5;
the molar ratio of the compound A-1 to the catalyst is 1: 0.2-1: 0.6;
the molar ratio of the compound A-1 to the alkali is 1: 1.5-1: 2.5;
the reaction solvent of the coupling reaction is an ether solvent.
3. The method according to claim 1, wherein, in the step 2,
the acid catalyst is one or more of concentrated sulfuric acid, acetyl chloride and thionyl chloride;
the R is2OH is one of methanol, ethanol, tertiary butanol and benzyl alcohol;
the molar ratio of the compound A-3 to the acidic catalyst is 1: 0.05-1: 0.3;
the compounds A-3 and R2The weight-volume ratio of OH is 1: 1-1: 10.
4. The method according to claim 1, wherein, in the step 3,
the base is a metal base;
the metal alkali is one or more of sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide and sodium tert-butoxide;
the reaction solvent of the double methylation reaction is an aprotic solvent;
the molar ratio of the compound A-4 to the methylating agent is 1: 2-1: 4;
the molar ratio of the compound A-4 to the metal base is 1: 2-1: 4;
the weight-volume ratio of the compound A-4 to the aprotic solvent is 1: 5-1: 15.
5. The method according to claim 1, wherein, in the step 4,
the iodination reagent for iodination reaction is one or more of N-iodosuccinimide and iodine simple substance;
the catalyst for the iodination reaction is concentrated sulfuric acid;
the reaction solvent of the iodination reaction is one or more of glacial acetic acid, dichloromethane, ethyl acetate and tetrahydrofuran.
6. The method of claim 2,
the step 1 specifically comprises the following steps: reacting the compounds A-1 and A-2 for 10-14 hours at the reaction temperature of 60-80 ℃ by taking an ether solvent as a solvent in the presence of a metal alkali and cuprous halide as a catalyst, hydrolyzing, and performing post-treatment to obtain a compound A-3;
wherein, the mol ratio of the compound A-1 to the compound A-2 to the cuprous halide to the metal alkali is 1 (1.5-2.5) to (0.2-0.6) to (1.5-2.5).
7. The method of claim 3,
the step 2 specifically comprises the following steps: the compound A-3 reacts with R in the presence of an acidic catalyst2Reacting OH at 40-65 ℃ for 4-5 hours, and performing post-treatment to obtain a compound A-4;
wherein the molar ratio of the compound A-3 to the acidic catalyst is 1: 0.05-1: 0.3; compounds A-3 and R2The weight-volume ratio of OH is 1: 1-1: 10.
8. The method of claim 4,
the step 3 specifically comprises the following steps: reacting the compound A-4 with a methylating agent in the presence of metal alkali at-10-25 ℃ for 5-7 hours by using an aprotic solvent as a solvent, hydrolyzing and carrying out post-treatment to obtain a compound A-5;
wherein the molar ratio of the compound A-4, the methylating agent and the metal base is 1 (2-4) to 2-4; the weight-volume ratio of the compound A-4 to the aprotic solvent is 1:5 to 1: 15.
9. The method of claim 5,
the step 4 specifically comprises the following steps: reacting the compound A-5 for 2-4 hours at 20-30 ℃ in the presence of an iodinated reagent, a catalyst and a reaction solvent, and performing aftertreatment to obtain an neratinib intermediate 2- (4-ethyl-3-iodo) phenyl-2-methylpropanoic acid;
wherein the molar ratio of the compound A-5 to the iodinating reagent is 1 (1.1-1.5); the weight volume ratio of the compound A-5 to the solvent is 1 (3-5); the weight volume ratio of the compound A-5 to the catalyst is 1 (1-2).
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