CN107098863B - Preparation method of gefitinib - Google Patents
Preparation method of gefitinib Download PDFInfo
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- CN107098863B CN107098863B CN201710386228.2A CN201710386228A CN107098863B CN 107098863 B CN107098863 B CN 107098863B CN 201710386228 A CN201710386228 A CN 201710386228A CN 107098863 B CN107098863 B CN 107098863B
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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Abstract
The invention discloses a synthetic method of high-purity gefitinib, which adopts 7-methoxy-6- (3-morpholine-4-yl propoxy) quinazoline-4 (3H) -ketone as a raw material to perform chlorination reaction with phosphorus oxychloride or phosphorus pentachloride, then performs condensation with 3-chloro-4-fluoroaniline to prepare a gefitinib crude product, and the gefitinib crude product is refined by a mixed solvent of methyl isobutyl ketone and ethyl acetate to obtain a gefitinib finished product.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, relates to drug synthesis, and particularly relates to a preparation method of gefitinib.
Background
Gefitinib (Gefitinib, ZD1839, trade name: Iressa) is represented by formula I:
chemical name: n- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine, an antineoplastic drug developed by Astra-Zeneca, England, which competes for the Mg-ATP binding site on the catalytic region of the epidermal growth factor receptor tyrosine kinase (EGFR-TK) on the cell surface, is a selective Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor, which is commonly expressed on solid tumors of epithelial origin.
Gefitinib widely inhibits growth of human tumor cells xenografted in nude mice, inhibits angiogenesis thereof, and can increase apoptosis of human tumor cell lines and inhibit invasion and secretion of angiogenesis factors in vitro. Gefitinib has been shown to enhance the antitumor activity of chemotherapy, radiation therapy and hormone therapy in animal experiments or in vitro studies.
Gefitinib is an anti-receptor molecule which inhibits EGFR generation signal transmission to cells by competing for Mg-ATP binding sites in the catalytic region of epidermal growth factor receptor tyrosine kinase (EGFR-TK) on the cell surface, inhibits EGFR to be combined with ligand to generate phosphorylation, inhibits other receptor molecules to form various homodimers or heterodimers, and further causes down regulation of activation of a downstream series of signal pathways such as IP13K/AKT and RAS/RAF/MAPK kinase pathways, and the like, thereby inhibiting tumor growth, metastasis and angiogenesis, and inducing apoptosis of tumor cells.
The drug is currently approved by the FDA to be used as a single-use therapy for patients with advanced non-cell lung cancer (NSCLC) which continues to deteriorate after chemotherapy, and the synthetic routes of gefitinib reported in the literature are mainly as follows:
route one: according to the report of K.N Gibbson (literature sources WO9633980, CN 96193526): according to the method, 6, 7-dimethoxy quinazolinone is used as a raw material, methyl on 6-methoxy group is selectively removed by methanesulfonic acid and L-methionine, hydroxyl is protected by acetyl, thionyl chloride chloro, 3-chloro-4-fluoroaniline is adopted for ammoniation and deprotection, and finally the obtained product reacts with halogenated-3-morphinylpropane to obtain gefitinib.
The disadvantage of this route is that selective removal of the 6-methoxy group requires the use of large amounts of methanesulfonic acid and L-methionine, which are not recovered and are environmentally polluting. Meanwhile, reaction raw materials are not easy to obtain, and the yield is lower.
And a second route: according to the reports of j.p. gildai and d. modi (literature source WO 2004024703): the method uses isovanillin as a raw material, firstly converts aldehyde group into cyano, then connects with 3-morpholine propyl, then nitrifies, reduces nitro group into amido, hydrolyzes cyano group into amide, closes ring, chloridizes, and finally connects with 3-chlorine-4-fluoroaniline to obtain gefitinib.
Although the method is improved and can be used for industrial production, the hydrolysis of the cyano group is difficult to control, the product of hydrolysis to acid is inevitable, meanwhile, the reaction steps are long, the side reactions are more, the impurity control difficulty is higher, and the raw materials are more expensive.
And a third route: literature sources CN 1733738:
the route takes 3, 4-dimethoxybenzoic acid as a raw material, and obtains a target product after nitration, demethylation, reduction, cyclization, chlorination and introduction of halogenated aromatic amine and alkyl side chain.
Although the method takes simple 3, 4-dimethoxybenzoic acid as a starting material, the method has the following two disadvantages: (1) according to the method, hydroxyl is not protected after methyl is removed, and the hydroxyl is an active group, so that the side reactions in the steps of reduction, cyclization, chlorination and the like are more, and the yield is low. (2) According to the fourth step of the synthetic route, 2-amino-4-methoxy-5-hydroxybenzoic acid directly reacts with formamide to construct a 4-carbonyl quinoline mother body ring, the number of byproducts in the step is large, and the yield is low.
The method is most similar to the method in the invention application in the way III (see patent document CN1733738), but the method adopts intermediate 6-hydroxy-7-methoxy-3, 4-dihydroquinazolin-4-ketone to perform chlorination, and the chlorinating agent in the chlorination mainly adopts thionyl chloride and DMF as a catalyst.
The preparation method disclosed in this patent document has the following disadvantages:
1) because unprotected hydroxyl exists on the benzene ring, the benzene ring is easy to be chlorinated, and the amination reaction of the benzene ring and 3-chloro-4-fluoroaniline is easy to generate dimer impurities and other impurities, as shown in the following formula:
2) the thionyl chloride is used as a chlorination reagent, and under the condition that DMF is used for catalyzing chlorination reaction, an impurity VI is easily generated, and the impurity reacts with 3-chloro-4-fluoroaniline to easily generate an impurity VII:
because the structure of the impurity VII is highly close to that of gefitinib, the impurity VII is extremely difficult to remove in subsequent refining treatment and is still difficult to meet the standard that the existing quality requirement is less than or equal to 0.1 percent after multiple times of crystallization, the structure of the impurity VII is avoided by controlling and changing a synthesis path and a method in the previous intermediate step, and the structures of the impurity VII and the gefitinib are compared as follows:
3) because of the strong corrosiveness and volatility of thionyl chloride, thionyl chloride is used as a chlorinating agent, so that the method has great damage to the corrosion of production equipment and the environment.
In summary, the gefitinib compound obtained by the preparation method reported in the prior art has the problems of more byproducts, complex post-treatment or repeated refining to meet the technical quality requirements of bulk drugs specified by ICH, and large environmental pollution, and is not suitable for industrial mass production, so a new technical scheme is urgently needed to provide better technical conditions, solve the product quality, continuously and stably produce bulk drugs meeting the existing technical quality requirements, and simultaneously reduce the environmental pollution in the production process to the lowest degree.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a preparation method of gefitinib, namely N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinylpropoxy) quinazoline-4-amine (formula I), which is characterized by comprising the following steps:
(1) taking 7-methoxy-6- (3-morpholine-4-yl propoxy) quinazoline-4 (3H) -ketone as an initial (formula II) raw material, and carrying out chlorination reaction with a chlorination reagent to obtain an intermediate I (formula III), wherein the chlorination reagent is POCl3Or PCl5，
(2) Carrying out substitution reaction on the intermediate I (formula III) and 3-chloro-4-fluoroaniline (shown as formula IV) to prepare a gefitinib crude product,
(3) and recrystallizing the crude gefitinib product and an organic solvent to obtain a pure gefitinib product.
Preferably, in the step (1), the solvent is acetonitrile or toluene;
preferably, in the step (1), the reaction temperature is preferably 60-90 ℃; further preferably, the reaction temperature is preferably 80-90 ℃;
preferably, in the step (1), the molar ratio of the 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazolin-4 (3H) -one (formula II) to the chlorinating agent is 1: 3-10, and more preferably 1: 4;
preferably, in the step (2), the solvent is isopropanol;
preferably, in the step (2), the reaction temperature is 60-90 ℃; further preferably, the reaction temperature is preferably 80-90 ℃;
preferably, in the step (2), the molar ratio of the intermediate I (formula III) to the 3-chloro-4-fluoroaniline is 1: 0.9 to 1.5; more preferably, the molar ratio of the intermediate I to the 3-chloro-4-fluoroaniline is 1: 1.05;
preferably, in the step (2), an acid-binding agent is further added in the substitution reaction of the intermediate I (shown in the formula III) and the 3-chloro-4-fluoroaniline, and the molar ratio of the use amount of the acid-binding agent to the use amount of the 3-chloro-4-fluoroaniline is 1-5: 1; more preferably, the molar ratio of the dosage of the acid-binding agent to the dosage of the 3-chloro-4-fluoroaniline is 2: 1;
more preferably, in the step (2), the acid-binding agent is potassium carbonate, sodium carbonate, triethylamine or other alkaline reagents;
preferably, in the step (3), the recrystallization organic solvent is one or a mixture of methyl isobutyl ketone and ethyl acetate.
Advantageous effects
1. The reaction steps and operation provided by the invention are very simple and convenient, the process complexity and the purification times are reduced, and the expanded production is easy to realize;
2. the product prepared by the method has extremely high purity which is more than or equal to 99.7 percent, the generation of impurity dimer and compound VIII is avoided, and the product quality is ensured;
3. the preparation method adopted by the invention avoids using thionyl chloride and other strong corrosive and volatile solvents, and reduces the environmental pollution to the maximum extent.
Drawings
FIG. 1 chemical structural formula of gefitinib;
FIG. 2 is a schematic diagram of a process for the preparation of intermediate one;
FIG. 3 is a scheme showing the preparation process of crude gefitinib.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings in conjunction with the following detailed description. It should be understood that the description is intended to be exemplary only, and is not intended to limit the scope of the present invention.
Example 1: intermediate one (formula iii): preparation of 4-chloro-7-methoxy-6- [3- (morpholin-4-yl) propoxy ] quinazoline hydrochloride
Adding 1.35L of toluene and 466.0ml of phosphorus oxychloride into a reaction tank, uniformly stirring, adding 319.3g of 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazolin-4 (3H) -one, adding 5ml of TEA, heating to 80-90 ℃, reacting for 1H, and monitoring by TLC (MeOH: DCM ═ 1:5, raw material R: 1: 5)f0.4, and Rf of the product is 0.6), the raw materials basically disappear, the solvent is distilled under reduced pressure at 55-60 ℃, most of the solvent is evaporated, the temperature is reduced after the distillation is finished, 3L of isopropanol is added for pulping for 1 hour at the temperature of 20-25 ℃, the mixture is filtered at room temperature, a filter cake is dried by drying, and the mixture is dried under reduced pressure at 50-60 ℃ for 8 hours to obtain 268.2g of light yellow solid, namely gefitinib intermediate 1, the yield is as follows: 79.4 percent. HPLC purity 98.5%.
Example 2: preparation of gefitinib crude product
121.3g of 3-chloro-4-fluoroaniline and 1.8L of isopropanol are added into a reaction pot, stirred until the mixture is completely dissolved, 219.6g of potassium carbonate is added, 268.2g of intermediate 1 is added, the mixture is stirred and heated to 80-85 ℃ for reflux reaction for 1h, TLC monitoring is carried out (MeOH: DCM 1:5, Rf of ZJ1 is 0.6, and Rf of the product is 0.8), and the raw material point disappears. Filtering while hot, cooling the filtrate to room temperature to obtain a solid, filtering, leaching a filter cake with 1.5L of isopropanol, spin-drying, and drying under reduced pressure at 50-60 ℃ for 6h to obtain a gefitinib crude product, wherein the yield is as follows: 94% and 99.3% HPLC purity.
Example 3: purification of crude gefitinib
333.5g of gefitinib crude product, 2L of methyl isobutyl ketone and 6L of ethyl acetate are added into a reaction tank, stirring is started, heating and refluxing are carried out for 3 hours, the mixture is dissolved and filtered while hot, the filtrate is naturally cooled to 20-25 ℃, crystallization is carried out for 24 hours under the condition of heat preservation, filtering is carried out, and filter cake is dried for 6 hours at 88-93 ℃ under reduced pressure (-0.08MPa) to obtain 273.5g of white crystalline powder, namely gefitinib fine product. mp: 193 ℃ and 195 ℃, yield: 82 percent. HPLC showed less than 0.1% single impurity.
Example 4: intermediate one (formula iii): preparation of 4-chloro-7-methoxy-6- [3- (morpholin-4-yl) propoxy ] quinazoline hydrochloride
Adding 1.35L of acetonitrile and 466.0ml of phosphorus oxychloride into a reaction tank, uniformly stirring, adding 319.3g of 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazoline-4 (3H) -ketone, adding 5ml of TEA, heating to 80-90 ℃, reacting for 1H, monitoring by TLC (MeOH: DCM (1: 5), Rf (0.4) as a raw material and Rf (0.6) as a product), basically disappearing the raw material, distilling at 55-60 ℃ under reduced pressure, evaporating most of solvent, cooling after distillation is finished, adding 3L of isopropanol at the temperature of 20-25 ℃, pulping for 1H, filtering at room temperature, drying filter cakes by spinning, drying at 50-60 ℃ under reduced pressure for 8H to obtain 274.6g of light yellow solid, namely gefitinib intermediate 1, wherein the yield is as follows: 81.3 percent. HPLC purity 98.0%.
Example 5: intermediate one (formula iii): preparation of 4-chloro-7-methoxy-6- [3- (morpholin-4-yl) propoxy ] quinazoline hydrochloride
Adding 1.35L of acetonitrile and 832g of phosphorus pentachloride into a reaction tank, uniformly stirring, adding 319.3g of 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazoline-4 (3H) -ketone, adding 5ml of TEA, heating to 80-90 ℃, reacting for 1H, monitoring by TLC (MeOH: DCM ═ 1:5, raw material Rf ═ 0.4, product Rf ═ 0.6), basically disappearing the raw materials, distilling at 55-60 ℃ under reduced pressure, evaporating most of solvent, cooling after distillation is finished, adding 3L of isopropanol at the temperature of 20-25 ℃, pulping for 1H, filtering at room temperature, drying a filter cake by spinning, and drying at 50-60 ℃ under reduced pressure for 8H to obtain 284.0g of light yellow solid, namely gefitinib intermediate 1, wherein the yield is 84.1%, and the purity HPLC is 98.3%.
Example 6: intermediate one (formula iii): preparation of 4-chloro-7-methoxy-6- [3- (morpholin-4-yl) propoxy ] quinazoline hydrochloride-control
Adding 328g of thionyl chloride and 30.0g of DMF2.86g into a reaction tank, uniformly stirring, adding 30.0g of 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazoline-4 (3H) -ketone, heating to 75-80 ℃, carrying out reflux reaction for 6H, monitoring by TLC (MeOH: DCM (1: 5), Rf (0.4) as a raw material and Rf (0.6) as a product), basically disappearing the raw material, carrying out reduced pressure distillation at 55-60 ℃, adding 61g of toluene after most of the solvent is evaporated, continuing to concentrate, repeating the operation twice, cooling after the distillation is finished, adding 119g of isopropanol at 20-25 ℃, pulping for 1H, filtering at room temperature, and carrying out spin-drying on a filter cake to obtain 24.3g of yellow solid, namely gefitinib intermediate 1, wherein the yield is 69.3%. HPLC purity 94.5%.
Example 7: preparation of gefitinib crude product-control group
10.4g of 3-chloro-4-fluoroaniline and 163ml of isopropanol were added to a reaction tank, and stirred until the mixture was completely dissolved, 19.8g of potassium carbonate was added, 24.3g of intermediate 1 (intermediate 1 obtained in example 6) was added, and the mixture was refluxed at 80 to 85 ℃ for 1 hour with stirring, followed by TLC monitoring (MeOH: DCM ═ 1:5, Rf of ZJ1 ═ 0.6, product Rf ═ 0.8), and the starting material point disappeared. Filtering while hot, cooling the filtrate to room temperature to obtain a solid, filtering, leaching a filter cake with 150ml of isopropanol, spin-drying, drying at 50-60 ℃ under reduced pressure for 6h to obtain a gefitinib crude product, 29.6g of a yellow solid, and obtaining the yield: 83.5 percent. The HPLC purity was 93.3% and the impurity VIII content was 1.7%.
Example 8: purification of crude gefitinib
Adding 29.6g of gefitinib crude product (crude product obtained in example 7) and 880ml of ethyl acetate into a reaction tank, stirring, heating and refluxing for 3 hours, dissolving and filtering while hot, naturally cooling the filtrate to 20-25 ℃, preserving heat and crystallizing for 24 hours, filtering, and drying the filter cake at 88-93 ℃ under reduced pressure (-0.08MPa) for 6 hours to obtain 22.7g of white crystalline powder, namely gefitinib fine product. The yield was 76.8%, the HPLC purity was 98.4%, and the impurity VIII content was 0.6%.
Claims (7)
1. A preparation method of gefitinib, namely a preparation method of N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinylpropoxy) quinazoline-4-amine hydrochloride (formula I), is characterized by comprising the following steps:
(1) taking 7-methoxy-6- (3-morpholine-4-yl propoxy) quinazoline-4 (3H) -ketone as an initial (formula II) raw material, carrying out chlorination reaction with a chlorinated reagent, wherein the solvent is acetonitrile, and obtaining an intermediate I (formula III), wherein the chlorinated reagent is PCl5，
(2) Carrying out substitution reaction on the intermediate I (formula III) and 3-chloro-4-fluoroaniline (formula IV), adding an acid-binding agent into isopropanol, wherein the acid-binding agent is potassium carbonate, sodium carbonate and triethylamine, the molar ratio of the use amount of the acid-binding agent to the use amount of the 3-chloro-4-fluoroaniline is 2:1, preparing a gefitinib crude product, the molar ratio of the intermediate I to the use amount of the 3-chloro-4-fluoroaniline is 1:1.05,
(3) and recrystallizing the crude gefitinib product and an organic solvent to obtain a pure gefitinib product, wherein the recrystallized organic solvent is ethyl acetate or a mixture of methyl isobutyl ketone and ethyl acetate in a volume ratio of 1: 3.
2. The method for preparing gefitinib according to claim 1, wherein in step (1), the reaction temperature is 60-90 ℃.
3. The method for preparing gefitinib of claim 2, wherein in step (1), the reaction temperature is 80-90 ℃.
4. The method for preparing gefitinib according to claim 1, wherein in step (1), the molar ratio of 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazolin-4 (3H) -one (formula II) to the chlorinating agent is 1: 3-1: 10;
5. the method of claim 4, wherein in step (1), the molar ratio of 7-methoxy-6- (3-morpholin-4-ylpropoxy) quinazolin-4 (3H) -one (formula II) to chlorinating agent is 1: 4.
6. The method for preparing gefitinib of claim 1, wherein in step (2), the reaction temperature is 60-90 ℃.
7. The method for preparing gefitinib of claim 6, wherein in step (2), the reaction temperature is 80-90 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101570516A (en) * | 2009-04-14 | 2009-11-04 | 重庆威尔德·浩瑞医药化工有限公司 | Method for preparing 4-(3-chlorine-4-fluorophenylalanine)-7-methoxy-6-[3-(4-morpholinyl) propoxy] quinazoline |
| CN101863844A (en) * | 2009-04-16 | 2010-10-20 | 翔真生物科技股份有限公司 | Synthesis method of 6,7-substituted-4-aniline quinazoline |
| CN102532042A (en) * | 2010-12-30 | 2012-07-04 | 上海医药工业研究院 | Aryl urea compound as well as intermediate and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101570516A (en) * | 2009-04-14 | 2009-11-04 | 重庆威尔德·浩瑞医药化工有限公司 | Method for preparing 4-(3-chlorine-4-fluorophenylalanine)-7-methoxy-6-[3-(4-morpholinyl) propoxy] quinazoline |
| CN101863844A (en) * | 2009-04-16 | 2010-10-20 | 翔真生物科技股份有限公司 | Synthesis method of 6,7-substituted-4-aniline quinazoline |
| CN102532042A (en) * | 2010-12-30 | 2012-07-04 | 上海医药工业研究院 | Aryl urea compound as well as intermediate and application thereof |
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