- Synthetic method of erlotinib
-
The invention relates to a synthetic method of erlotinib, and belongs to the technical field of chemical synthesis. The preparation method comprises the following synthesis steps: (1) reacting a compound I with 2-chloroethyl methyl ether to generate a compound II; (2) oxidizing the compound II through peracetic acid to generate a compound III; (3) reacting the compound III with benzene sulfonyl chloride to generate a compound IV; (4) carrying out a ring closing reaction on the compound IV, ammonium chloride and formamide to generate a compound V; (5) reacting the compound V with phosphorus oxychloride to generate a compound VI; and (6) reacting the compound VI with m-aminophenylacetylene to generate a compound VII erlotinib. The invention provides a new synthetic route, and the used raw materials are common materials, are simple and easily available, can adapt to production of various scales, and the synthetic method has good industrial production prospects.
- -
-
Paragraph 0083-0085
(2020/07/12)
-
- Method for synthesizing erlotinib intermediate with microchannel reactor
-
The invention discloses a method for synthesizing an erlotinib intermediate with a microchannel reactor, belongs to the field of synthesis of anti-tumor drugs in organic synthesis and solves the problems of low yield, poor purity, high energy consumption,
- -
-
Paragraph 0052; 0062; 0068; 0071-0072; 0082; 0105-0111; 0122
(2018/09/08)
-
- Synthesis and evaluation of novel 18F-labeled quinazoline derivatives with low lipophilicity for tumor PET imaging
-
Four novel 18F-labeled quinazoline derivatives with low lipophilicity, [18F]4-(2-fluoroethoxy)-6,7-dimethoxyquinazoline ([18F]I), [18F]4-(3-((4-(2-fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine ([18F]II), [18F]4-(2-fluoroethoxy)-7-methoxy-6-(2-methoxyethoxy)quinazoline ([18F]III), and [18F]4-(2-fluoroethoxy)-6,7-bis(2-methoxyethoxy)quinazoline ([18F]IV), were synthesized via a 2-step radiosynthesis procedure with an overall radiochemical yield of 10% to 38% (without decay correction) and radiochemical purities of >98%. The lipophilicity and stability of labeled compounds were tested in vitro. The log P values of the 4 radiotracers ranged from 0.52 to 1.07. We then performed ELISA to measure their affinities to EGFR-TK; ELISA assay results indicated that each inhibitor was specifically bounded to EGFR-TK in a dose-dependent manner. The EGFR-TK autophosphorylation IC50 values of [18F]I, [18F]II, [18F]III, and [18F]IV were 7.732, 0.4698, 0.1174, and 0.1176?μM, respectively. All labeled compounds were evaluated via cellular uptake and blocking studies in HepG2 cell lines in vitro. Cellular uptake and blocking experiment results indicated that [18F]I and [18F]III had excellent cellular uptake at 120-minute postinjection in HepG2 carcinoma cells (51.80?±?3.42%ID/mg protein and 27.31?±?1.94%ID/mg protein, respectively). Additionally, biodistribution experiments in S180 tumor-bearing mice in vivo indicated that [18F]I had a very fast clearance in blood and a relatively high uptake ratio of tumor to blood (4.76) and tumor to muscle (1.82) at 60-minute postinjection. [18F]III had a quick clearance in plasma, and its highest uptake ratio of tumor to muscle was 2.55 at 15-minute postinjection. These experimental results and experiences were valuable for the further exploration of novel radiotracers of quinazoline derivatives.
- Chong, Yan,Chang, Jin,Zhao, Wenwen,He, Yong,Li, Yuqiao,Zhang, Huabei,Qi, Chuanmin
-
-
- An efficient method for reduction of nitroaromatic compounds to the corresponding aromatic amines with NH2NH2·H2O catalysed by H2O2-treated activated carbon
-
An efficient and green protocol for the reduction of nitroaromatic compounds to the corresponding amines has been developed. The reduction catalyst system includes NH2NH2·H2O and H2O2-treated activated carbon. Without adding additional metals, the H2O2-treated activated carbon could be reused for many cycles without decreasing catalytic efficiency. The aromatic amines could be obtained in good to excellent yields.
- Jiang, Yuqin,Suo, Huajun,Zhang, Dandan,Li, Xiyong,Sun, Yamin,Ren, Baoqi,Zhang, Weiwei,Xu, Guiqing
-
p. 509 - 512
(2017/10/03)
-
- Preparation method of erlotinib intermediate
-
The invention belongs to the field of chemical synthesis and relates to a preparation method of an erlotinib intermediate 6,7-di(methoxyethoxy)quinazoline-4-one. According to the invention, by screening reaction conditions, a preparation technology of the
- -
-
Paragraph 0028
(2018/03/01)
-
- Model quinazoline chlorethazine compound and its preparation method and application for treating tumor (by machine translation)
-
A novel quinazoline nitrogen mustard compound is characterized in that: one end is provided with a nitrogen mustard alkylating group; the other end is provided with a 6, 7-substituted quinazoline structure; a substituent R1 is located at a site 4 of a quinazoline matrix, and represents 2-, 3-, 4- nitrogen mustard substituent; and substituents R2, R3 are located at site 6 and 7 of a quinazoline matrix, and represent methoxyethoxy, methoxy, morpholine propoxy, 3-etrahydrofuran oxygen group and hydroxyl group. The compound has a structure shown as a formula A. Experiments show that the compound can cause cross-linking of DNA, and is a bifunctional alkylating agent. In vivo antitumor activity experiment show that the compound has good activity; furthermore, the compound has the advantage of low toxicity, which a nitrogen mustard drug is lack of. At the same time, the compound is easy for synthesis, has high total yield. Advantages of the compound show that it has great potential to become a drug for treatment of cancer.
- -
-
-
- Erlotinid hydrochloride method for the preparation of key intermediate
-
The invention discloses a preparation method of an erlotinib hydrochloride key intermediate 4-chloro-6,7-di(2-methoxyethoxy)quinazoline, which comprises the following steps: reacting the raw material ethyl 3,4-dihydroxybenzoate with ethyl 2-methoxysulfonate, nitrating, reducing, cyclizing and chlorinating to obtain the key intermediate 4-chloro-6,7-di(2-methoxyethoxy)quinazoline. The method has the advantages of mild reaction conditions, low cost, high purity and high total yield (up to 74.8%), and can easily implement industrial production.
- -
-
Paragraph 0065; 0066
(2016/11/09)
-
- Isolation of highly pure erlotinib hydrochloride by recrystallization after nucleophilic substitution of an impurity with piperazine
-
Optimized synthesis and purification of erlotinib hydrochloride (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine hydrochloride) were studied. Highly polar piperazine was used in a nucleophilic substitution reaction with the chlorinated intermediate byproduct N-(3-ethynylphenyl)-6(2- chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. As a result, N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was completely transformed to N-(3-ethynylphenyl)-6(2- piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The polarity of N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy) quinazolin-4-amine hydrochloride was changed, and its molecule was enlarged. It was easy to remove this larger, more polar, compound by recrystallization. Highly pure erlotinib hydrochloride was obtained with low impurity content (99.9 %.
- Zhang, Gengzhen,Zha, Linlin
-
p. 2303 - 2309
(2013/07/26)
-
- Design and synthesis of novel quinazoline nitrogen mustard derivatives as potential therapeutic agents for cancer
-
Thirteen novel quinazoline nitrogen mustard derivatives were designed, synthesized and evaluated for their anticancer activities in vitro and in vivo. Cytotoxicity assays were carried out in five cancer cell lines (HepG2, SH-SY5Y, DU145, MCF-7 and A549) and one normal human cell line (GES-1), in which compound 22b showed very low IC50 to HepG2 (the IC50 value is 3.06 μM), which was lower than Sorafenib. Compound 22b could inhibit cell cycle at S and G2/M phase and induce cell apoptosis. In the HepG2 xenograft model, 22b exhibited significant cancer growth inhibition with low host toxicity in vivo.
- Li, Shilei,Wang, Xiao,He, Yong,Zhao, Mingxia,Chen, Yurong,Xu, Jingli,Feng, Man,Chang, Jin,Ning, Hongyu,Qi, Chuanmin
-
p. 293 - 301
(2013/10/01)
-
- 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)
-
- QUINAZOLINE DERIVATIVES AS RAF KINASE MODULATORS AND METHODS OF USE THEREOF
-
Compounds according to formula (I), compositions and methods are provided for modulating the activity of RAF kinases, including BRAF kinase and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by RAF kinases. Formula (I): or a pharmaceutically acceptable salt, solvate, clathrate of hydrate thereof, wherein X is O or S(O)t; Ra is O or S.
- -
-
Page/Page column 174-175
(2009/10/22)
-
- Syntheses of 4-(indole-3-yl)quinazolines - A new class of epidermal growth factor receptor tyrosine kinase inhibitors
-
The epidermal growth factor (EGF) family of membrane receptors has been identified as a key element in the complex signaling network that is utilized by various classes of cell-surface receptors. The synthesis and pharmacological results of 4-(indole-3-yl)quinazolines are described. The synthesized compounds are new high potent EGFR-tyrosine kinase inhibitors with excellent cytotoxic properties at different cell lines. Furthermore the 4-(indole-3-yl)quinazolines show some tendencies to inhibit the HER-2 TK, too. Moreover this substance class has remarkable strong fluorescence properties.
- Lueth, Anja,Loewe, Werner
-
p. 1478 - 1488
(2008/09/21)
-
- PROCESS FOR PRODUCING 6,7-BIS(2-METHOXYETHOXY)-QUINAZOLIN-4-ONE
-
A process comprising a reaction of ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate with a formic acid compound in the presence of an ammonium carboxylate gives 6,7-bis(2-methoxyethoxy)quinazolin-4-one in a high yield.
- -
-
Page/Page column 7
(2008/06/13)
-
- COMPOUND INHIBITING IN VIVO PHOSPHORUS TRANSPORT AND MEDICINE CONTAINING THE SAME
-
An objective of the present invention is to provide compounds that can effectively suppress the concentration of phosphorus in serum to effectively prevent or treat diseases induced by an increase in concentration of phosphate in serum. The compounds according to the present invention are compounds represented by formula (I) and pharmaceutically acceptable salts and solvates thereof: wherein A represents an optionally substituted five- to nine-membered unsaturated carbocyclic moiety or a five- to nine-membered unsaturated heterocyclic moiety, and ---- represents a single bond or a double bond, R5 represents optionally substituted aryl or the like, Z represents - N=CHR6R7 or the like, R6 and R7 represent H, optionally substituted alkyl, optionally substituted aryl or the like, R101 and R102 together form =O, and R103 and R104 represent H, or R101 and R104 together from a bond, and R102 and R103 together form a bond.
- -
-
Page/Page column 194-195
(2010/11/08)
-
- 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)
-
- 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)
-
- Aniline derivatives
-
The invention concerns aniline derivatives of formula I STR1 wherein m is 1, 2 or 3, n is 0, 1, 2 or 3, Q is phenyl or naphthyl or a 5- or 6-membered heteroaryl moiety containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, and X, R1 and R2 are defined in the claims; or pharmaceutical compositions containing them, and the methods of using the compounds as tyrosine kinase inhibitors and for the treatment of proliferative diseases such as cancer.
- -
-
-