- Novel preparation of gefitinib
-
A new synthesis of the anticancer drug gefitinib is described starting from methyl 3-hydroxy-4-methoxybenzoate.The sequence involves alkylation of the starting material, followed by nitration, reduction, cyclisation, chlorination and amination reactions.
- Zheng, Youguang,Li, Mingdong,Zhang, Shaoning,Ji, Min
-
-
Read Online
- Synthesis of gefitinib from methyl 3-hydroxy-4-methoxy-benzoate
-
This paper reports a novel synthesis of gefitinib starting from methyl 3-hydroxy-4-methoxybenzoate. The process starts with alkylation of the starting material, followed by nitration, reduction, cyclization, chlorination and two successive amination reactions. The intermediates and target molecule were characterized by 1H-NMR, 13C-NMR, MS and the purities of all these compounds were determined by HPLC. This novel synthetic route produced overall yields as high as 37.4%.
- Ming, Dong Li,You, Guang Zheng,Ji, Min
-
-
Read Online
- Improved protocol for synthesis of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy) quinazolin-4-amine (gefitinib)
-
An improved three-step process for the synthesis of gefitinib from readily available starting material is discussed in this protocol. The protocol is based on the synthesis, isolation, characterization of novel intermediates and their application in the alkylation step for the synthesis of gefitinib. Excellent results were achieved over the conventional synthetic methodologies. Isolation of these intermediates were effective in replacing high boiling solvent with low boiling solvent(s) but also in eliminating base from the reaction. These conditions led to effective elimination of all the prior art reported impurities. This high-yielding process is cost-effective with isolable and stable intermediates. These intermediates were characterized using NMR, mass spectroscopy, DSC and XRPD analyses.
- Kumar, Pawan,Mazlee, Muhammad Taufiq F.,Abdul Wahab, Muhammad K.,Belwal, Chandra Kant,Kumar, Ramesh,Sajid, Shahnawaz
-
-
Read Online
- Synthesis of [11C]Iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase
-
Iressa (Gefitinib) is an orally active inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK) involved in cell signal transduction processes critical to proliferation, apoptosis, repair, and angiogenesis of cancer cells. [11C]Iressa was first designed and synthesized as a new potential positron emission tomography (PET) cancer imaging agent for EGFR-TK in 30-40% radiochemical yield with 4.0-6.0 Ci/μmol specific activity at end of bombardment (EOB).
- Wang, Ji-Quan,Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
-
-
Read Online
- A new synthesis of gefitinib
-
A four-step synthesis of the FDA-approved anticancer agent gefitinib was developed starting from 2,4-dichloro-6,7-dimethoxyquinazoline. Reaction temperatures were highly practical (0-55 °C), and chromatographic purifications were avoided. The ionic liquid trimethylammonium heptachlorodialuminate was used to monodemethylate the dimethoxyquinazoline core. In the final step, a selective dehalogenation was employed to provide gefitinib in 14% overall yield on a gram scale.
- Maskrey, Taber S.,Kristufek, Tyler,Laporte, Matthew G.,Nyalapatla, Prasanth R.,Wipf, Peter
-
-
Read Online
- A Different Approach to the EGFR Inhibitor Gefitinib Involving Solid-Phase Synthesis
-
An efficient solid-phase synthesis approach is here reported for the first time to prepare the EGFR inhibitor Gefitinib. The five-step synthetic strategy used FMP resin as the solid support, and FTIR and colorimetric assays were used to track the reaction's progress. Gefitinib was obtained with an overall yield of 40%.
- Sequeira, André,Louren?o, Ana,Ferreira, Luísa Maria,Branco, Paula Sério,Mendes, Zita,Louren?o, Nuno M. T.,Figueiredo, Margarida,Carvalho, Luísa C. R.
-
-
Read Online
- Method suitable for industrial production and preparation of gefitinib
-
The invention discloses a method suitable for industrial production and preparation of gefitinib, which takes 6, 7-dimethoxy-3H-quinazoline-4-one as a raw material, and gefitinib is obtained through four steps of chlorination, amination, demethylation and reaction with N-(3-chloropropyl) morpholine, so as to solve the problems that the existing synthetic route is complex and long, the total yield is low, a large number of environment-unfriendly reagents are used, and the technology cannot be amplified. According to the method, pyridine hydrochloride/DMSO is utilized to remove 6-position methyl in a high-selectivity manner, a key intermediate N-(3-chloro-4-fluorophenyl)-6-hydroxy-7-methoxyquinazoline-4-amine is obtained in a high yield manner, and convenient synthesis of the intermediate is realized. The synthesis method has the advantages of cheap and easily available raw materials and short route, and gefitinib and derivatives modified by different 6-site groups can be rapidly obtained. The preparation method solves the bottleneck problem of large-scale production of the active pharmaceutical ingredient gefitinib.
- -
-
Paragraph 0022; 0032
(2021/08/19)
-
- Synthesis of gefitinib
-
The invention relates to preparation of gefitinib. Specifically, 3-morpholine propane-1-ol (formula I) reacts with 6-halogenated-N-(4-chloro-2-fluorophenyl)-7-methoxyquinazoline-4-amine (formula II) in the presence of a copper reagent, an alkali, an additive and a solvent, so the preparation of the gefitinib is realized.
- -
-
Paragraph 0021-0026
(2021/09/29)
-
- Purification process of gefitinib
-
The invention provides a purification process of gefitinib. The purification process comprises the following steps: adding potassium carbonate, potassium iodide and a gefitinib intermediate 4-(3-chloro-4-fluoroaniline)-7-methoxyquinazolin-6-ol into N, N-dimethylformamide, stirring, heating to 70 DEG C, adding N-(3-chloropropyl)morpholine, reacting to obtain a gefitinib reaction solution, adding diluted hydrochloric acid into the gefitinib reaction solution, cooling to room temperature, adding sodium chloride, stirring for crystallization, filtering to obtain filter cake, adding the filter cakeinto a sodium bicarbonate solution, carrying out alkali washing, and recrystallizing the obtained product in ethanol to obtain high-purity gefitinib. The purification process is simple in process, and the obtained gefitinib product is high in purity.
- -
-
Paragraph 0038; 0045-0085
(2020/08/25)
-
- Synthesis method of tumor cell inhibition drug
-
The invention relates to the technical field of organic synthesis and drugs, and discloses a synthesis method of a tumor cell inhibition drug. 3-hydroxy-4-methoxybenzaldehyde is taken as a starting raw material, aldehyde ortho-hydrogen is activated through a temporary guide group to facilitate amino substitution, [4 + 2] cyclization addition reaction is combined for cyclization, and introduction of a propyl morpholine side chain to a hydroxyl group, chlorination and introduction of a fluorochloroaniline side chain are sequentially carried out to finally prepare gefitinib. The synthesis path ofthe tumor cell inhibition drug gefitinib reduces reaction steps, shortens the reaction time, reduces the production cost, reduces the generation of impurities in the system, and reduces the emissionof three wastes.
- -
-
Paragraph 0042; 0052-0053; 0054; 0064-0065
(2020/02/29)
-
- A high-purity of gefitinib preparation method
-
The invention relates to a process for preparing high-purity of gefitinib method the method comprises the following 5 steps: 1st step exotic fragrance orchid [...], 2nd step etherification, 3rd step nitration, step reduction 4th, 5th step ring gathers passes through purification of the final product is obtained. The programme raw material sources are extensive, the cost is reduced, improving the quality of products, it is easy to further popularization and application.
- -
-
-
- A preparation method of gefitinib (by machine translation)
-
The present invention relates to organic chemical and medical technology field, in particular relates to a preparation method of gefitinib. The present invention provides a preparation method of gefitinib, obtained by formula I compounds, the formula I compound preparation method comprises the following steps: nitration reaction, oxidation reaction, selective demethylation reaction, reduction reaction, a cyclization reaction, phenolic hydroxyl acetylation reaction. The present invention provides a preparation method can at the same time reducing the cost, it is easy for the refined purification, easy preparation and control of related impurities, the overall preparation process routes are greatly optimized, is suitable for industrial scale production. (by machine translation)
- -
-
Paragraph 0119-0122
(2019/05/16)
-
- Synthesis method of aza-arylamine compound and aza-arylamine compound
-
The invention provides a synthesis method of an aza-arylamine compound as shown in a formula (I). The synthesis method comprises the following steps: an aza aromatic hydrocarbon compound as shown in aformula (II) reacts with an amine compound as shown in a formula (III) in presence of alkali and under a heating condition, so that u X substituent groups on an A ring of the compound as shown in theformula (II) are substituted by NRR in the compound as shown in the formula (III), and the compound as shown in the formula (I) is obtained, wherein A is an aza six-membered aromatic ring or five-membered aromatic ring, and is an independent single ring or is fused with a ring B; X refers to that the A ring has at least n X substituent groups, each X substituent group is independently selected from the group consisting of F, Cl, Br, I, CN, alkoxy of C and alkylthio of C, and n is a positive integer selected from 1-5; and the alkali is one or a mixture of more selected fromof BuOK, BuONa, BuONa, KHMDS, NaHMDS and LiHMDS. The synthesis method provided by the invention does not need the use of transition metal catalysts, is simple and convenient to operate, is economical and practical and is environmentally friendly. In addition, the invention also provides the aza-arylamine compound prepared by the method.
- -
-
Paragraph 0101; 0108; 0109; 0110
(2019/04/26)
-
- Anticancer-Active N-Heteroaryl Amines Syntheses: Nucleophilic Amination of N-Heteroaryl Alkyl Ethers with Amines
-
A mild amination protocol of N-heteroaryl alkyl ethers with various amines is described. This transformation is achieved by utilizing simple and readily available base as promoter via C-O bond cleavage, offering a new amination strategy to access several anticancer-active compounds. This work is highlighted by the excellent functional group compatibility, scalability, wide substrate scope, and easy derivatization of a variety of drugs.
- Wang, Xia,Yang, Qiu-Xia,Long, Cheng-Yu,Tan, Yan,Qu, Yi-Xin,Su, Min-Hui,Huang, Si-Jie,Tan, Weihong,Wang, Xue-Qiang
-
supporting information
p. 5111 - 5115
(2019/07/03)
-
- New synthesis method of gefitinib
-
The invention relates to a new synthetic method of an anti-tumor drug 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholinylpropoxy)quinazoline (gefitinib, I). According to the synthesis method,synthesis is performed through a novel synthetic intermediate. Before a quinazoline mother ring is synthesized, hydroxy of 3-hydroxy-4-methoxybenzonitrile is reacted with 3-morpholinopropyl chloride firstly, so that the steps of adding protecting groups and removing the protecting groups are reduced, the synthesis route is shortened, the step number of synthesis is lowered, raw materials are cheapand easily obtained, the use of chlorinated reagents which heavily pollute the environment is avoided, the purification process is simplified, the pH (potential of hydrogen) value does not need to berepeatedly adjusted, the operation is safe and simple, and the reaction yield exceeds 60%.
- -
-
-
- Efficient preparation method of gefitinib
-
The invention provides an efficient preparation method of gefitinib. 2-nitro-4,5-dimethoxybenzonitrile is used as a starting material and subjected to a demethylation reaction, a substitution reaction, a nitro reduction reaction, a ring forming reaction, an amino substitution reaction and the like to obtain a finished gefitinib product. By means of the preparation method, gefitinib with the purityhigher than 99.9% can be obtained, the total yield of the preparation method is 61-75%, raw materials used in the method are low in price, there are only five steps in the process route, the operation is simple and easy to control, the yield of the target product is high, and the repeatability is good.
- -
-
-
- A method for preparing gefitinib, a tyrosine kinase inhibitor
-
The invention discloses a method for preparing gefitinib that is a tyrosine kinase inhibitor, and belongs to the fields of medicines and fine chemical engineering. The method is a novel preparation scheme, and can prepare a target compound meeting requirements no matter from which intermediate. The method has advantages of short steps, simple reaction operation, high safety and reliability, a highyield, a low cost, high product purity, low pollution, simple operation, and the like.
- -
-
Paragraph 0096; 0097; 0098
(2018/03/26)
-
- Preparation method of gefitinib
-
The invention discloses a preparation method of gefitinib. The preparation method is characterized in that a cyclizing step for synthesizing quinoline stem nuclei is improved, the reaction yield in the cyclization process is relatively high, the obtained compound 2, namely 7-methoxy-6-[3-(4-morpholine)propoxy]-4-quinazolinamine, is subjected to a diazo reaction to generate diazo salt, and then thediazo salt is subjected to a halogenation to obtain a compound 3, and the component 3 reacts with 3-chloro-4-fluoroaniline to obtain gefitinib, wherein the reactions in the route are mostly classicalreactions, the yield is high, the purity is high, and the side reactions are few. The synthetic route is shortened, strong-polluting chlorinating agents such as sulfoxide chloride or phosphorus oxychloride is prevented from being used, the reagent is relatively easy to get, the reagent cost is low, the chlorinating agents are relatively environmental-friendly, and the preparation method is suitable for industrial production.
- -
-
Paragraph 0085-0086
(2018/11/22)
-
- 4 - (3 - chloro - 4 - fluoro benzyl amidogen) - 7 - methoxy - 6 - (3 - morpholino-propoxy) quinazoline preparation method
-
The invention provides a preparation method of 4-(3-chloro-4-fluorophenyl amido)-7-methoxy-6-(3-morpholine propoxy) quinazoline. Specifically, according to the method, 3-hydroxy-4-methoxybenzaldehyde (isovanillin) serves as raw materials, and the target product (I) is synthesized through the steps of oxidation, esterification, amidation, cyclization and the like. The method has the advantages of being short in synthetic route, low in cost, environmentally friendly, short in reaction step, easy to operate, high in yield and product purity and the like, and therefore the preparation method is suitable for industrial production.
- -
-
-
- An anti-cancer drug preparation method
-
The invention discloses a novel synthesis method of an anticancer medicine gefitinib. The preparing method includes subjecting 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile that is adopted as a raw material to reduction by sodium hydrosulfite, salifying with hydrochloric acid, reacting with N,N-dimethylformamide dimethyl acetal to obtain a condensation product, subjecting the condensation product and 3-chloro-4-fluoroaniline to cyclization to obtain the gefitinib. The initial raw material adopted by the preparing method is cheap and easily available. The synthesis route is simplified. The raw material utilization rate and the total yield are largely increased. Reaction intermediates are mostly purified by a recrystallization method or are directly used for a next reaction. The method has characteristics of high yield, less three-waste in reaction processes and low cost, and is suitable for industrial production.
- -
-
-
- Practical and efficient synthesis of gefitinib through selective O-alkylation: A novel concept for a transient protection group
-
A practical process that includes a simple four-step procedure for the preparation of gefitinib (1), a tyrosine kinase inhibitor that targets the epidermal growth factor receptor, is described. Dramatic improvements over previously reported conventional synthetic procedures were achieved. We found effective coupling conditions to minimize the inevitable production of an N-alkylated side product, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)-quinazoline-4-amine (3) using a transient trimethylsilyl protecting group. We synthesized gefitinib in an 81.1% overall yield from a commercially available starting material on a multigram scale using a route that did not require work-up of any of the reaction steps.
- Kang, Sung Kwon,Lee, Seung Wook,Woo, Daekoo,Sim, Jaehoon,Suh, Young-Ger
-
supporting information
p. 1990 - 1998
(2017/09/27)
-
- Quinazoline derivative and application thereof
-
The invention belongs to the field of medical chemistry, and particularly relates to 4-anilino quinazoline derivative with 1-methyl-2-nitro-5-methylene imidazole. The structure of the 4-anilino quinazoline derivative is shown as a graph, wherein an R represents a compound shown as a graph or -(CH)R, the n is equal to 2 or 3 or 4 or 5 or 6, and an R represents morpholino or piperidyl or pyrrolidyl or piperazinyl or dimethylamino; an R represents a compound shown as a graph or hydrogen; an R, an R and an R respectively independently selectively represent hydrogen or chlorine or fluorine or bromine or acetenyl or trifluoromethylphenol. The 4-anilino quinazoline derivative has the advantage that as shown by pharmacological experiments, effects of inhibiting tumor cell proliferation can be realized by the 4-anilino quinazoline derivative which is a compound and pharmaceutically acceptable salt of the 4-anilino quinazoline derivative.
- -
-
Paragraph 0015
(2017/08/28)
-
- Synthetic method for gefitinib
-
The invention specifically relates to a synthetic method for 4-(3-chloro-4-fluorophenylamido)-7-methoxy-6-(3-morpholinylpropyl)quinazoline (gefitinib, I), belonging to the technical field of pharmaceutical chemistry. The synthetic method is characterized in that 3-morpholinylpropanol is used as a starting material and reacts with methylbenzenesulfonyl chloride so as to obtain a compound II; and the compound II and a gefitinib intermediate 4-(3-chloro-4-fluorophenylamido)-6-hydroxy-7-methoxy-quinazoline are subjected to etherification under proper conditions so as to obtain the target product gefitinib.
- -
-
Paragraph 0035-0037
(2017/07/21)
-
- Preparation method gefitinib
-
The invention belongs to the field of pharmaceutical chemistry, and more specifically relates to a synthesis method of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine (gefitinib, I). According to the synthesis method, 3-morpholinyl propanol is taken as an initial material, a compound II is obtained via reaction of 3-morpholinyl propanol with methanesulfonyl chloride; and the compound II and gefitinib intermediate 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline are subjected to etherification etherification reaction under appropriate conditions so as to obtain target product gefitinib.
- -
-
Paragraph 0031; 0035-0037
(2017/07/20)
-
- Method for synthesizing gefitinib
-
The invention discloses a method for synthesizing high-purity gefitinib. 7-methoxy-6-(3-morpholine-4-yl-propoxy)quinazoline-4(3H)-one as a raw material and phosphorus oxychloride or phosphorus pentachloride undergo a chlorination reaction, then the reaction product and 3-chloro-4-fluoroaniline undergo a condensation reaction to produce a gefitinib crude product, and the gefitinib crude product is refined by a mixed solvent of methyl isobutyl ketone and ethyl acetate to form a gefitinib finished product. The method has the advantages of mild reaction conditions, simple operation and small environmental pollution and can produce high purity medicinal gefitinib satisfying the existing technical quality requirements.
- -
-
Paragraph 0053-0054
(2017/09/26)
-
- Synthetic method of 4-(3-chlorine-4-fluorophenyl)-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline
-
The invention discloses a synthetic method of 4-(3-chlorine-4-fluorophenyl)-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline. The synthetic method comprises the following steps that 3-hydroxy-4-methoxy benzonitrile serves as the raw material and reacts with 3-chloropropyl morpholine, and 4-methoxyl-3-[3-(4-morpholinyl) propoxy] cyanobenzene is obtained; the 4-methoxyl-3-[3-(4-morpholinyl) propoxy] cyanobenzene is nitrified with mixed acid, and 2-nitryl-4-methoxyl-5-[3-(4-morpholinyl) propoxy] cyanobenzene is obtained; the 2-nitryl-4-methoxyl-5-[3-(4-morpholinyl) propoxy] cyanobenzene is subjected to reduction, and then 2-amino-4-methoxyl-5-[3-(4-morpholinyl) propoxy] cyanobenzene is obtained; 3-chlorine-4-fluoroaniline reacts with an imine complex, N'-(3-chlorine-4-phenyl)-N, N-dimethyl formamidine is obtained, and the imine complex is prepared from DMF and dimethyl sulfate through heating and a reaction; 2-amino-4-methoxyl-5-[3-(4-morpholinyl) propoxy] cyanobenzene reacts with the N'-(3-chlorine-4-fluorophenyl)-N, N-dimethyl formamidine, so that the 4-(3-chlorine-4-fluorophenyl)-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline is obtained. The synthetic method has the advantages of being environmentally friendly and high in yield.
- -
-
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF GEFITINIB
-
The present invention relates to a modified process for preparing Gefitinib (4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline) represented by chemical formula I, which provides high cost-efficiency, high yield and high purity. More particularly, the present invention provides a modified process for preparing Gefitinib, which comprises carrying out condensation of 4-(3′-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-ol represented by chemical formula II with 3-morpholinopropyl chloride represented by chemical formula III in the presence of an inorganic basic compound by using an alkali metal iodide and 18-crown-6 as a catalyst.COPYRIGHT KIPO 2016
- -
-
Paragraph 0064; 0075; 0076
(2017/04/11)
-
- Preparation method of gefitinib
-
The invention discloses a preparation method of gefitinib, and belongs to the technical field of chemical pharmacy. The method provided by the invention has the following steps: carrying out esterolysis on a compound I at first to obtain a compound II, and then carrying out condensation reaction between the compound II and N-(3-chloropropyl) morpholine to obtain a compound III. According to the preparation method provided by the invention, high-pressure hydrogenation, cyanation, and nitro reduction are avoided, the reaction condition is mild and controllable, the reaction step is relatively short, the yield is relatively high, and the cost is relatively low, so that the preparation method is suitable for industrial production. The teaction formula is shown in the specification.
- -
-
Paragraph 0067; 0068; 0069; 0070
(2016/10/10)
-
- Preparation method of gefitinib
-
The invention discloses a preparation method of gefitinib. The preparation method comprises steps as follows: 1) on the presence of anion exchange resin, 6-(2-morpholino ethyoxyl)-7-methoxy-3,4-dihydroquinazolin-4-ketone and sulfonyl chloride have a contact reaction in acetonitrile, quenching is performed through ice water after the reaction ends, dichloromethane extraction and reduced pressure concentration are performed, and 6-(2-morpholino ethyoxyl)-4-chloro-7-methoxyquinazoline is obtained, wherein the temperature of a contact reaction is 55-60 DEG C; 2) 6-(2-morpholino ethyoxyl)-4-chloro-7-methoxyquinazoline obtained in the step 1), nickel chloride and TMEDA (tetramethylethylenediamine) are added to a reaction container and stirred for 20-30 min, 3-chloro-4-fluoroaniline is added and has a substitution reaction in THF (tetrahydrofuran) at the temperature of 50-55 DEG C, and gefitinib is obtained. By means of the method for preparing gefitinib, the product yield can be greatly improved, the steps are reasonable, the conditions are mild, and fewer byproducts are produced.
- -
-
Paragraph 0026; 0032; 0033; 0035
(2016/10/10)
-
- Gefitinib and its derivatives of the new method for microwave synthesis
-
The invention discloses a new method for performing microwave synthesis on gefitinib and a derivative thereof. The method comprises the following steps of: at first, synthesizing 6-methoxyl-7-hydroxyl quinazoline-4-one from 2-iodo (bromo)-4-methoxyl-5-hydroxyl cyanophenyl used as an initial raw material and formamidine hydrochloride in a microwave mode; then performing reaction with 4-(3-bromo propyl) morpholine to introduce an alkyl side chain so as to obtain 7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline-4-ketone; in the presence of a catalyst, performing reaction on the obtained product and a chlorination reagent to obtain 4-chloro-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline; finally, performing reaction on 4-chloro-7-methoxyl-6-[3-(4-morpholinyl) propoxy] quinazoline and 3-chloro-4-fluoroaniline to obtain a final product 4-(3-chloro-4-fluoroanilino)-7-methoxyl-6-(3-morpholinyl propoxy) quinazoline (gefitinib). The whole route steps are simplified into four steps, the yield is high, the method is convenient to carry out, the dangerousness is low, and the application of high-pollution reagents is reduced; moreover, the whole route is high in economy and suitable for industrial production, and the product cost is reduced. The reaction formula is as shown in the specification.
- -
-
Paragraph 0043-0045
(2016/12/22)
-
- Preparation method of medicine for treating lung cancer
-
The invention provides a preparation method of a medicine for treating a lung cancer. Specifically, according to the method, 5-(3-morpholinyl propoxy)-6-methoxyisatin (II) is used as a raw material, and oxidation, substitution, chlorination and substitution are performed to synthesize a target product (I). The method has the advantages of short synthetic route, simplicity in experiment operation, environmental friendliness, high atom economy, good yield and effect and the like, and therefore, the method is suitable for industrial production.
- -
-
Paragraph 0106; 0125; 0126
(2017/01/12)
-
- Gefitinib preparation method
-
The invention discloses a gefitinib preparation method. The method is characterized in that an intermediate quinazoline-4-ketone is chlorinated into 4-chloroquinazoline through a chlorating agent; a solvent and the unreacted chlorating agent are removed by evaporation after the reaction is over, a product is not separated or purified, alkali, N-bromine propyl morpholine and fluorochloroaniline are added directly to perform secondary reaction, a solvent is added after the reaction is over to precipitate a crude product, and the net product gefitinib is obtained after recrystallization and refining. According to the method, a one-pot synthesis mode is adopted, a preparation process is simple and easy to operate, the total recovery, yield and purity are high, the production cost is low, industrial production is performed easily, and the practicality is high.
- -
-
Paragraph 0037; 0038
(2017/02/09)
-
- N '-aryl-N, N-dimethyl-formamidine new method for the preparation of (by machine translation)
-
The present invention provides a synthetic N '-aryl-N, N-dimethyl-formamidine of the new method. The method firstly to N, N-dimethyl formamide and dimethyl sulfate to imine salt; generating imide salt in the presence of an alkali, and aromatic amine reaction generating N '-aryl-N, N-dimethyl-carboximidamide; the amidines same with other amine function generating [...] compound, can be used in the anti-tumor drug AKT, synthesis of lapatinib and gefitinib, and the like. Mild reaction conditions of the method, is suitable for industrial production. (by machine translation)
- -
-
Paragraph 0094-0096
(2017/02/17)
-
- Novel Crystalline Form Of Gefitinib And Method for Preparing the Same
-
In the present invention, provided are a novel crystal foam of 4-(3andprime;-chloro-4andprime;-fluoro anilino)-7-methoxy-6- (3-morpholino propoxy) quinazoline compound well known as gefitinib and a manufacturing method thereof. The gefitinib of the present invention is an anticancer agent for inhibiting epidermal growth factor receptor (EGFR) of cancer cells and treats cancers by blocking signals related to the growth of the cancer cell. In addition, the gefitinib is used for treating lung cancers which are divided into small cell lung cancers and non-small cell lung cancers.COPYRIGHT KIPO 2015
- -
-
-
- PROCESS FOR PREPARING QUINAZOLINE DERIVATIVE
-
A concise, efficient and cost-and time-saving process for the preparation of a quinazoline derivative of formula (A) given below: which is an intermediate for making gefitinib or gefitinib itself, comprising reacting a compound of formula (B): with 3-chloro-4-fluoroaniline (VI) in the presence of a N,N-dialkyl formamide acetal, a Bronsted acid catalyst, and a solvent in a one-pot reaction.
- -
-
Paragraph 0035; 0038; 0039
(2016/01/01)
-
- A simple and highly efficient process for synthesis of Gefitinib and its intermediate
-
A highly efficient one pot conversion of 4-methoxy-3-benzyloxy-6-nitro benzoate to 6-benzoyloxy-7-methoxy quinazoline-4-one using Fe/acetic acid and formamidine acetate followed by debenzylation of 4-(3-chloro-4-flurophenylamino)-6-benzoyloxy-7-methoxy quinazoline using methanesulfonic acid in chloroform is described. Additionally the desmethyl impurity formation is controlled using oxalyl chloride and DIPEA.
- Kumar, Neeraj,Chowdhary, Anil,Gudaparthi, Omprakash,Patel, Nilesh G.,Soni, Sanjay K.,Sharma, Pradeep
-
p. 1269 - 1274
(2014/12/10)
-
- PROCESS FOR PREPARING GEFITINIB AND AN INTERMEDIATE USED FOR PREPARING THEREOF
-
This invention relates to a method of preparing gefitinib and an intermediate used therein. In the method of preparing gefitinib, the production of an N-alkylated impurity can be suppressed via a simple process, and thus, gefitinib having high purity can be obtained with high efficiency without a complicated separation process such as chromatography, thereby enabling the effective mass production of gefitinib.
- -
-
-
- QUINAZOLINE INHIBITORS OF EGFR TYROSINE KINASE
-
The present invention relates to new quinazoline inhibitors of EGFR tyrosine kinase, pharmaceutical compositions thereof, and methods of use thereof.
- -
-
-
- A novel approach to quinazolin-4(3H)-one via quinazoline oxidation: an improved synthesis of 4-anilinoquinazolines
-
A novel strategy to prepare 4-anilinoquinazoline derivatives based on the oxidation of the quinazoline ring is described. Quinazoline oxidation has been investigated and improved, thus leading to an efficient and high yielding method to quinazolin-4(3H)-ones. Efficiency of this approach has been evaluated synthesizing four well known tyrosine kinase inhibitors and comparing the obtained yields with those achievable through conventional synthetic methods.
- Marzaro, Giovanni,Guiotto, Adriano,Pastorini, Giovanni,Chilin, Adriana
-
experimental part
p. 962 - 968
(2010/03/25)
-
- A PROCESS FOR THE PREPARATION OF GEFITINIB
-
The present invention provides an improved, industrial advantageous process for the preparation of gefitinib of formula (I), and its pharmaceutically acceptable salts thereof in high yield and purity.
- -
-
Page/Page column 18
(2010/08/04)
-
- Method of Synthesizing 6,7-Substituted 4-Anilino Quinazoline
-
A method of synthesizing 6,7-substituted 4-anilino quinazoline employs 3,4-substituted benzoic acid as an initial reactant, and the 6,7-substituted 4-anilino quinazoline is obtained by an esterifying step, a nitrating step, a reducing step, a cyclizing step, and an one-pot reaction. In the above method, the initial reactant has low cost and yield. of the 6,7-substituted 4-anilino quinazoline is high, therefore, production cost can be reduced effectively, and competitive power of the product of the 6,7-substituted 4-anilino quinazoline can be improved.
- -
-
Page/Page column 7
(2010/11/03)
-
- PROCESS FOR THE PREPARATION OF GEFITINIB
-
There is provided a compound of formula (III), and a process for preparing a compound of formula (V) comprising converting a compound of formula (III) to the compound (V), wherein (X) is fluoro, chloro, bromo or iodo. There is also provided a process for preparing a compound of formula (Xl) comprising converting a compound of formula (X) to the compound (Xl). The compounds (V) and (Xl) so prepared may be used in a process for preparing gefitinib.
- -
-
Page/Page column 27
(2008/12/08)
-
- One-pot conversion of 2-nitrobenzonitriles to quinazolin-4(3H)-ones and synthesis of gefitinib and erlotinib hydrochloride
-
A simple and efficient one-pot conversion of 2-nitrobenzonitriles to quinazolin-4(3H)-ones involving reduction, formylation, hydrolysis and cyclization is reported. These quinazolinones have been used for making in economical way the anticancer drug molecules gefitinib (Iressa) and erlotinib HCl (Tarceva).
- Chandregowda, Venkateshappa,Venkateswara Rao, Gudapati,Chandrasekara Reddy, Goukanapalli
-
-
- Convergent approach for commercial synthesis of gefitinib and erlotinib
-
An efficient, economical and large-scale convergent synthesis of epidermal growth factor receptor- tyrosine kinase inhibitors gefitinib (1, Iressa) and erlotinib (2, Tarceva) approved by U.S. FDA for the treatment of non-small-cell lung cancer is described. The formation of 4-anilinoquinazolines are achieved in a simple one-pot reaction of suitable forniamidine intermediates and substituted anilines involving Dimroth rearrangement, thereby avoiding the need to make quinazolin-4(3H)-one intermediates, which require a large experimental inputs. Using this process, we have produced drug candidates 1 with overall yield of 66% from 4-methoxy-5-[3-(4-morpholinyl) propoxy]-2-nitrobenzonitrile (3) and 2 with 63% from 4-bis(2-methoxyethoxy)-2-nitrobenzonitrile (6) on a multigram scale.
- Chandregowda, Venkateshappa,Rao, Gudapati Venkateswara,Reddy, Goukanapalli Chandrasekara
-
p. 813 - 816
(2012/12/30)
-
- Improved synthesis of gefitinib and erlotinib hydrochloride- anticancer agents
-
A highly efficient and commercially viable process for the synthesis of 6,7-dihydroxy-4-anilinoquinazoline derivatives gefitinib (1) and erlotinib hydrochloride (2), used for the treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer, is reported. This new process has improved yields and avoids the unstable 4-chloroquinazoline intermediate. The intermediates and final products were characterized by 1H and 13C nuclear magnetic resonance (NMR), mass spectra (MS), and elemental analysis, and purities of final products were determined by high performance liquid chromatogram (HPLC) and potentiometric titration methods. Copyright Taylor & Francis Group, LLC.
- Chandregowda, Venkateshappa,Rao, Gudapati Venkateswara,Reddy, Goukanapalli Chandrasekara
-
p. 3409 - 3415
(2008/02/13)
-
- Improved synthesis of substituted 6,7-dihydroxy-4-quinazolineamines: Tandutinib, erlotinib and gefitinib
-
The synthesis of three substituted 6,7-dihydroxy-4-quinazolineamines: tandutinib (1), erlotinib (2) and gefitinib (3) in improved yields is reported. The intermediates were characterized by NMR and the purities determined by HPLC.
- Knesl, Petr,Roeseling, Dirk,Jordis, Ulrich
-
p. 286 - 297
(2007/10/03)
-
- CANCER TREATMENT METHOD
-
The present invention relates to a method of treating cancer in a mammal by administration of 4-quinazolinamines and at least one additional EGFR and/or erbB-2 inhibitor. In particular, the method relates to methods of treating cancers by administration of N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amino} methyl)-2-furyl]-4-quinazolinamine and salts and solvates thereof in combination with at least one additional EGFR and/or erbB-2 inhibitor.
- -
-
Page/Page column 26-27
(2010/10/20)
-
- Fluorine-18 labeling of 6,7-disubstituted anilinoquinazoline derivatives for positron emission tomography (PET) imaging of tyrosine kinase receptors: Synthesis of18F-Iressa and related molecular probes
-
Inhibitors of tyrosine kinase enzymatic activity represent a promising new class of antineoplastic agents. Although clinical studies performed over the last decade give more insight on the potential therapeutic applications of such drugs, identification of the individual patients who might benefit from them remains a major challenge. We have developed a synthetic strategy for the production of a wide variety of radiolabeled 6,7-disubstituted 4-anilinoquinazolines suitable for noninvasive imaging of tyrosine kinase receptors to predict therapy effectiveness. Three new F-18 labeled radiopharmaceuticals based on the therapeutic agents Tarceva, Iressa, and ZD6474 were synthesized. Decay-corrected yields varied between 25 and 40% for a total synthesis time of 120 min, thus providing F-18 labeled tyrosine kinase inhibitors in quantities and times practical for use as PET radiopharmaceuticals. Copyright
- Seimbille, Yann,Phelps, Michael E.,Czernin, Johannes,Silverman, Daniel H. S.
-
p. 829 - 843
(2007/10/03)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF GEFITINIB
-
Present invention discloses an improved process for the preparation of gefitinib (4-(3'-chloro-4'-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline), of formula-I, which comprises: (i) etherification of iso-vanillin with 3-morpholinopropyl halide, (ii) nitration using nitric acid, (iii) oximation, (iv) dehydration, (v) reduction-cum-hydrolysis, (vi) quinazolinone formation, (vii) introduction of a leaving group at C-4 position in quinozolinone, and (viii) condensation with 3-chloro4-fluoroaniline to get the crude gefitinib. Purification of crude gefitinib is achieved via acid/base treatment or by crystallization from solvents such as ethyl acetate, isopropanol, acetonitrile, and methyl ethyl ketone. Formula I, IX, XI, XIII, XV and XVI.
- -
-
Page/Page column 28; 30
(2010/02/13)
-
- PROCESS FOR THE MANUFACTURE OF GEFITINIB
-
The invention relates to a process for the manufacture of 4-(3'-chloro-4'- fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline which comprises the rearrangement reaction optionally in the presence of a suitable catalyst of 3-(3'-chloro-4'-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin- 4-imine of Formula (II).
- -
-
Page/Page column 16
(2008/06/13)
-
