Preparation method of icotinib hydrochloride
By using 3,4-dihydroxybenzamide as a starting material and introducing an amide group, the instability of the nitration reaction in the synthesis route of icotinib hydrochloride was solved, the yields of compounds II and IV were improved, and the production cost was reduced.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- CHONGQING SHENGHUAXI PHARMA CO LTD
- Filing Date
- 2026-02-03
- Publication Date
- 2026-05-19
AI Technical Summary
In the existing synthetic routes for icotinib hydrochloride, the nitration reaction is unstable, resulting in low yield and high cost for industrial production.
Using 3,4-dihydroxybenzamide as the starting material, an amide group is introduced, and the stability of the intermediate product and the yield of the ring-closing reaction are improved through a stable nitration reaction and a pyrimidine ring formation process.
The yields of compound II and compound IV were both above 95%, resulting in a significant increase in overall yield and a reduction in industrial production costs.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, specifically a method for preparing icotinib hydrochloride. Background Technology
[0002] Icotinib is a novel drug independently developed by Betta Pharmaceuticals and approved for marketing in August 2011. Lung cancer is one of the most common cancers in my country. Icotinib hydrochloride is a first-generation targeted therapy with good efficacy and low toxicity, mainly used to treat patients with non-small cell lung cancer carrying EGFR mutations. Icotinib hydrochloride works through mechanisms such as inhibiting EGFR tyrosine kinase, inducing tumor cell apoptosis, blocking signal transduction pathways, enhancing anti-tumor immune responses, and inhibiting tumor angiogenesis. Its chemical name is N-(3-alkynylphenyl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxanedodecano[2,3-G]quinazoline-4-amine hydrochloride, and its chemical structure is shown below:
[0003] Molecular formula: C 22 H 22 ClN3O4 Molecular weight: 427.89 CAS No.: 1204313-51-8.
[0004] There are two main methods for preparing icotinib, as reported in domestic and international literature and patents: Prior art 1: The synthetic route reported in patent CN105237510 is as follows: ; The route involves reacting 3,4-dihydroxybenzonitrile with 1,8-bis(p-toluenesulfonate)-3,6-dioxooctane to obtain 3,4-benzo-12-crown-4-benzonitrile, followed by nitration to reduce the nitro group to an amino group, yielding compound C. Compound C then reacts with N,N-dimethylformamide dimethyl acetal to obtain compound D. Compound D is then salted with m-aminophenylacetylene to obtain icotinib hydrochloride.
[0005] In the route reported in the patent, the preparation method of compound B shows that the cyano group is unstable under the nitration conditions of concentrated sulfuric acid and is prone to side reactions to generate carboxyl groups. The yield after crystallization and purification is only 67%, which is low. In addition, the yield of the final step reaction to form the cyclization reaction of icotinib is only about 80%, which is also low and the cost of industrial production is high.
[0006] Prior art 2: The synthetic route reported in patent CN101878218 is as follows: ; The route involves reacting ethyl 3,4-dihydroxybenzoate with 1,8-bis(p-toluenesulfonate)-3,6-dioxooctane to obtain ethyl 3,4-benzo-12-crown-4-benzoate, followed by nitration to reduce the nitro group to an amino group, yielding compound 3. Compound 3 undergoes a cyclization reaction with ammonium formate and ammonium acetate to obtain compound 4. Compound 4 undergoes a chlorination reaction with phosphorus oxychloride to obtain compound 5. Compound 5 undergoes a substitution reaction with m-aminophenylacetylene to obtain icotinib.
[0007] In the route reported in the patent, the preparation method of compound 2 involves ethyl benzoate, which is unstable under the nitration conditions of concentrated sulfuric acid and during the post-treatment process. It is prone to side reactions that generate carboxyl groups, and the yield after crystallization and purification is only 65.7%, which is low. In addition, the yield of chlorination reaction using phosphorus oxychloride is only about 77%, which is also low. Therefore, the overall yield is low and the cost of industrial production is high.
[0008] In summary, the methods reported in Existing Technology 1 and Existing Technology 2 both have low yields for the nitration reaction, mainly due to the instability of the ethyl benzoate structure. Both methods result in low overall yields and high costs for industrial production. Summary of the Invention
[0009] The purpose of this invention is to address the shortcomings of existing icotinib hydrochloride technology by providing a simple, high-yield, high-purity, and relatively economical method for large-scale industrial production.
[0010] The present invention achieves two objectives by introducing a stable group: firstly, it prevents the benzene ring from being easily hydrolyzed during nitration; secondly, it is a group that can undergo ring-closure reactions during the subsequent formation of the pyrimidine ring. The present invention has found that amide groups can achieve the above objectives.
[0011] To achieve the technical objective of this invention, the following technical solution is provided: This invention uses commercially available 3,4-dihydroxybenzamide as a starting material to prepare icotinib hydrochloride, and the route is as follows: .
[0012] Specifically, the following steps are included: The reaction formula for step 1 is as follows: .
[0013] Starting with 3,4-dihydroxybenzamide, an etherification ring-forming reaction was carried out with 1,8-di(p-toluenesulfonate)-3,6-dioxooctane to obtain compound I. Specifically, 3,4-dihydroxybenzamide was dissolved in solvent 1, a base was added, the mixture was heated and stirred for 30 min, and then 1,8-di(p-toluenesulfonate)-3,6-dioxooctane was added dropwise. After the reaction was completed, post-treatment was performed to obtain compound I. In step 1, during the preparation of compound I, the molar ratio of 3,4-dihydroxybenzamide to 1,8-bis(p-toluenesulfonate)-3,6-dioxooctane is 1:1.1 to 1.4, preferably (1:1.1 to 1.3). Step 1 uses solvent 1 selected from one or a mixture of several of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), acetonitrile, dimethyl sulfoxide (DMSO), and ethylene glycol dimethyl ether (DME); The alkali used in step 1 is selected from one or a mixture of sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate; In step 1, the molar ratio of 3,4-dihydroxybenzamide to alkali is 1:4 to 7, preferably (1:4 to 5).
[0014] The reaction formula for step 2 is as follows: ; Compound I obtained in step 1 was dissolved in solvent 2, and nitric acid and sulfuric acid were added at 0-5℃ to carry out a nitration reaction. After the reaction was completed, post-treatment was performed to obtain compound II.
[0015] In step 2, during the preparation of compound II, solvent 2 is selected from one or a mixture of acetic acid and trifluoroacetic acid; In step 2, the acids used to prepare compound II are sulfuric acid and nitric acid. In step 2, during the preparation of compound II, the molar ratio of compound I to sulfuric acid is 1:6 to 9, preferably (1:7 to 8). In step 2, during the preparation of compound II, the molar ratio of compound I to nitric acid is 1:9 to 12, preferably (1:10 to 11).
[0016] The reaction formula for step 3 is as follows: ;
[0017] Compound II obtained in step 2 was dissolved in solvent 3, 10% Pd / C was added, and the nitro group was reduced by hydrogenation. After the reaction was completed, compound III was obtained by post-treatment.
[0018] In step 3, during the preparation of compound III, solvent 3 is selected from one or a mixture of methanol, ethanol, acetonitrile, and tetrahydrofuran; In step 3, during the preparation of compound III, the mass-volume ratio of compound II to solvent is 1:5 to 10, preferably (1:6 to 8). In step 3, during the preparation of compound III, the mass ratio of compound II to Pd / C is 1:0.05 to 0.1, preferably (1:0.06 to 0.08).
[0019] The reaction formula for step 4 is as follows: ; Compound III obtained in step 3 was dissolved in solvent 4 to carry out a cyclization reaction. After the reaction was completed, post-treatment was performed to obtain compound IV.
[0020] In step 4, during the preparation of compound IV, solvent 4 is selected from one or a mixture of several of DMF, N-methylpyrrolidone, acetonitrile, and tetrahydrofuran; In step 4, during the preparation of compound IV, the mass-volume ratio of compound III to solvent is 1:5 to 8, preferably (1:5 to 7). In step 4, during the preparation of compound IV, the molar ratio of compound III to formaldehyde is 1:2 to 4, preferably (1:2 to 3).
[0021] The reaction formula for step 5 is as follows: ; Compound IV obtained in step 4 was dissolved in solvent 5, and phosphorus oxychloride was used as the chlorination reagent. After the reaction was completed, post-treatment was performed to obtain compound V.
[0022] In step 5, during the preparation of compound V, solvent 5 is selected from one or a mixture of several of dichloromethane, trichloromethane, 1,2-dichloroethane, and tetrahydrofuran; In step 5, during the preparation of compound V, the mass-volume ratio of compound IV to solvent is 1:15 to 20, preferably (1:16 to 18). In step 5, during the preparation of compound IV, the molar ratio of compound IV to phosphorus oxychloride is 1:8 to 12, preferably (1:10 to 11).
[0023] The reaction formula for step 6 is as follows: ;
[0024] Compound V obtained in step 5 was dissolved in solvent 6, and 3-aminophenylacetylene was added to carry out a substitution reaction. After the reaction was completed, post-treatment was performed to obtain icotinib hydrochloride.
[0025] In step 6, during the preparation of icotinib hydrochloride, solvent 6 is selected from one or a mixture of several of ethanol, methanol, isopropanol, acetonitrile, and tetrahydrofuran; In step 6, during the preparation of icotinib hydrochloride, solvent 6 is mixed with 1-5% by volume of DMF as a co-solvent. In step 6, during the preparation of icotinib hydrochloride, the mass-volume ratio of compound V to solvent is 1:25-30, preferably (1:25-27). In step 6, during the preparation of icotinib hydrochloride, the molar ratio of compound V to 3-aminophenylacetylene is 1:1.1 to 1.8, preferably (1:1.1 to 1.5).
[0026] This invention provides a method for preparing icotinib hydrochloride, which has the following main advantages: This invention uses 3,4-dihydroxybenzamide instead of the starting materials (ethyl 3,4-dihydroxybenzoate and 3,4-dihydroxybenzonitrile) reported in existing literature and patents. This starting material is more stable in subsequent reactions, less prone to hydrolysis, and can obtain compound II of this invention in a yield of over 95%, which is significantly higher than the 65-77% yield of the prior art.
[0027] This invention uses 3,4-dihydroxybenzamide as the starting material and cleverly introduces an amide group, which not only ensures the good structural stability of the subsequent intermediate products, but also achieves a yield of over 92% for compound IV during the ring-closing process to form a pyrimidine ring. This yield is significantly higher than the 80% yield of the prior art.
[0028] This invention overcomes the shortcomings of existing technologies for icotinib hydrochloride, such as low overall yield and high production cost. Detailed Implementation
[0029] To further understand the present invention, the preparation method of icotinib hydrochloride provided by the present invention will be described in detail below with reference to embodiments. It should be understood that these embodiments are described only to further illustrate the features of the present invention, and not to limit the scope of the present invention or the scope of the claims.
[0030] Example 1: Preparation of Compound I 100 g (0.653 mol) of 3,4-dihydroxybenzamide was dissolved in 2000 mL of DMF. 360 g (2.61 mol) of potassium carbonate was added, and the mixture was stirred for 30 min. The temperature was raised to 80 °C, and 329 g (0.718 mol) of 1,8-bis(p-toluenesulfonate)-3,6-dioxooctane (dissolved in 200 mL of DMF) was slowly added. After the addition was complete, the reaction was continued for 1 h. The reaction was monitored for completeness by TLC. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove excess potassium carbonate, and the solvent was removed by vacuum distillation. The residue was extracted with 1000 mL of ethyl acetate, and the ethyl acetate was removed by vacuum distillation. The residue was then extracted three more times with 300 mL of petroleum ether. The petroleum ether extracts were combined and evaporated to dryness under vacuum to give 80 g of compound I with an HPLC purity of 98.5% and a yield of 46%. m / z [M+H] + : 268.28.
[0031] Preparation of Compound II Compound I (80 g, 0.3 mol) was dissolved in 240 mL of acetic acid. The solution was cooled to 0–5 °C, and 270 g of concentrated nitric acid was slowly added. Then, 206 g of concentrated sulfuric acid was added dropwise at 0–5 °C. The reaction was continued at this temperature for 1.5 h. After the reaction was complete, the reaction solution was slowly added to 3 L of ice water, stirred for 30 min, filtered, washed, and dried to obtain 90 g of compound II with an HPLC purity of 98% and a yield of 96%. m / z [M+H] + 313.27.
[0032] Preparation of Compound III Compound II (80 g, 0.256 mol) was added to an autoclave, followed by 500 mL of methanol and 5.6 g of 10% Pd / C. After purging the air with N2, a hydrogenation reaction was carried out at a hydrogen pressure of 0.1-0.2 MPa for 3 h at room temperature (20-25 °C). After the reaction was complete, the mixture was filtered, and the filtrate was evaporated to dryness. 200 mL of methyl tert-butyl ether was added, and the mixture was slurried, filtered, and dried to obtain 66 g of compound III with an HPLC purity of 99% and a yield of 92%. m / z [M+H] + : 283.29.
[0033] Preparation of compound IV Compound III (66 g, 0.234 mol) was added to a reaction flask, followed by 340 mL of DMF and 14 g of paraformaldehyde. The mixture was heated to 95-100 °C and reacted for 5 h. After the reaction was complete, the reaction solution was cooled to room temperature and added to 800 mL of ice water. The mixture was stirred for 1 h, filtered, and dried to obtain 62 g of compound IV with an HPLC purity of 99% and a yield of 90%. m / z [M+H] + : 293.29.
[0034] Preparation of compound V Compound IV (62 g, 0.212 mol) was added to a reaction flask, followed by 1000 mL of chloroform and 325 g of phosphorus oxychloride. The mixture was heated to 35 °C and reacted for 5 h. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure. Then, 500 mL of chloroform was added and slowly added to 500 mL of ice water. The pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was stirred for 30 min. The layers were separated, yielding a chloroform layer. The aqueous layer was extracted twice more with 300 mL of chloroform each time. The chloroform layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain 56 g of compound V with an HPLC purity of 98% and a yield of 85%. m / z [M+H] + 311.73.
[0035] Preparation of icotinib hydrochloride Compound V (56 g, 0.18 mol) was added to a reaction flask, followed by 1400 mL of ethanol, 23 g of 3-aminophenylacetylene, and 15 mL of DMF. The mixture was then heated to 75-80 °C and reacted for 5 h. After the reaction was complete, the reaction solution was evaporated to dryness under reduced pressure. 500 mL of ethyl acetate was added, and the ethyl acetate layer was washed with 300 mL of water. The ethyl acetate was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain 73 g of icotinib hydrochloride with an HPLC purity of 99% and a yield of 95%. m / z [M+H] + 392.42.
Claims
1. A method for preparing icotinib hydrochloride, comprising the following steps: ； The reactions include, in sequence, etherification, nitration, nitro reduction, pyrimidine cyclization, chlorination, and substitution salt formation.
2. The preparation method according to claim 1, wherein the reaction formula in step 1 is as follows: ； Starting with 3,4-dihydroxybenzamide, it was reacted with 1,8-bis(p-toluenesulfonate)-3,6-dioxooctane to form an ether ring, yielding compound I. Specifically, 3,4-dihydroxybenzamide was dissolved in solvent 1, a base was added, and the mixture was heated and stirred for 30 min. Then, 1,8-bis(p-toluenesulfonate)-3,6-dioxooctane was added dropwise. After the reaction was completed, post-treatment was performed to obtain compound I. in, The molar ratio of 3,4-dihydroxybenzamide to 1,8-bis(p-toluenesulfonate)-3,6-dioxooctane used in step 1 is 1:1.1 to 1.3; In step 1, solvent 1 is selected from one or a mixture of several of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), acetonitrile, dimethyl sulfoxide (DMSO), and dimethyl glycol ether (DME); In step 1, the alkali used is selected from one or a mixture of sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate. In step 1, the molar ratio of 3,4-dihydroxybenzamide to alkali is 1:4 to 5.
3. The preparation method according to claim 1, wherein the reaction formula in step 2 is as follows: ； Compound I obtained in step 1 was dissolved in solvent 2, and nitric acid and sulfuric acid were added at 0-5℃ to carry out a nitration reaction. After the reaction was completed, post-treatment was performed to obtain compound II. in, Solvent 2 used in step 2 is selected from one or a mixture of acetic acid and trifluoroacetic acid; In step 2, the acids used are sulfuric acid and nitric acid. In step 2, the molar ratio of compound I to sulfuric acid is 1:7 to 8. In step 2, the molar ratio of compound I to nitric acid is 1:10 to 11.
4. The preparation method according to claim 1, wherein the reaction formula in step 3 is as follows: ； Compound II obtained in step 2 was dissolved in solvent 3, 10% Pd / C was added, and the nitro group was reduced by hydrogenation. After the reaction was completed, the compound III was obtained by post-treatment. in, Step 3 uses solvent 3 selected from one or a mixture of several of methanol, ethanol, acetonitrile, and tetrahydrofuran; In step 3, the mass-volume ratio of compound II to solvent is 1:6 to 8. In step 3, the mass ratio of compound II to Pd / C is 1:0.06 to 0.
08.
5. The preparation method according to claim 1, wherein the reaction formula in step 4 is as follows: ； Compound III obtained in step 3 was dissolved in solvent 4 and subjected to a cyclization reaction. After the reaction was completed, post-treatment was performed to obtain compound IV. in, Step 4 uses solvent 4 selected from one or a mixture of several of DMF, N-methylpyrrolidone, acetonitrile, and tetrahydrofuran; In step 4, the mass-volume ratio of compound III to solvent is 1:5 to 7. In step 4, the molar ratio of compound III to formaldehyde is 1:2 to 3.
6. The preparation method according to claim 1, wherein the reaction formula in step 5 is as follows: ； Compound IV obtained in step 4 was dissolved in solvent 5, and phosphorus oxychloride was used as the chlorination reagent. After the reaction was completed, post-treatment was performed to obtain compound V. in, Step 5 uses solvent 5 selected from one or a mixture of several of dichloromethane, trichloromethane, 1,2-dichloroethane, and tetrahydrofuran; In step 5, the mass-volume ratio of compound IV to solvent is 1:16 to 18. In step 5, the molar ratio of compound IV to phosphorus oxychloride is 1:10 to 11.
7. The preparation method according to claim 1, wherein the reaction formula in step 6 is as follows: ； Compound V obtained in step 5 was dissolved in solvent 6, and 3-aminophenylacetylene was added to carry out a substitution reaction. After the reaction was completed, post-treatment was performed to obtain icotinib hydrochloride. in, Step 6 uses solvent 6 selected from one or a mixture of several of ethanol, methanol, isopropanol, acetonitrile, and tetrahydrofuran; In step 6, solvent 6 is mixed with 1-5% by volume of DMF as a co-solvent. In step 6, the mass-volume ratio of compound V to solvent is 1:25 to 27. In step 6, the molar ratio of compound V to 3-aminophenylacetylene is 1:1.1 to 1.5.