cas 179688-29-0, 6,7-Bis-(2-methoxyethoxy)-4(3H)-quinazolinone

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Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors
The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
Chen, Zhe-Sheng,Dai, Qing-Qing,Li, Guo-Bo,Liu, Hong-Min,Liu, Hui,Wang, Bo,Wang, Shaomeng,Yu, Bin,Yuan, Shuo,Zhang, Jing-Ya,Zhang, Xiao-Nan,Zuo, Jia-Hui
p. 14895 - 14911
(2021/10/12)

Catalytic cyclization preparation method and application of erlotinib key intermediate
The invention relates to a catalytic cyclization preparation method and application of an erlotinib key intermediate. By using 2-nitro-4, 5-bis (2-methoxyethoxy) ethyl benzoate as a raw material and adopting a polysaccharide-loaded nano-palladium catalyst, the erlotinib key intermediate 6, 7-bis (2-methoxyethoxy)-4-quinazolinone is prepared through a one-pot method. The erlotinib key intermediate is applied to preparation of quinazoline ring compounds. The method is carried out by adopting a catalytic one-pot method, the catalyst can be recycled for more than 10 times, the post-treatment is simple, the product purity is high, the next reaction can be directly carried out, the operation is simple, the pollution is less, and the cost is low. The method solves the problems of high catalyst price, high separation difficulty, high metal residue, more reaction three wastes and the like in the original process, greatly reduces the cost, provides technical guarantee for development of an industrial production process of erlotinib, and also provides a new reference method for synthesis of other anti-tumor drugs with quinazoline structures.
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Paragraph 0022; 0033-0042

(2021/11/06)

Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities
A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.
Zhang, Zixue,Zhang, Qingwei,Zhang, Hao,Jiao, Minru,Guo, Zheng,Peng, Xinyan,Fu, Lei,Li, Jianqi
(2021/10/16)

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.
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(2020/07/12)

Preparation method of erbtinib
The invention discloses a preparation method of erbtinib. The method comprises the following steps: carrying out a cyclization reaction on a compound represented by formula 1 to obtain a compound represented by formula 2, carrying out a chlorination reaction on the compound of the formula 2 to obtain a compound represented by formula 3, and carrying out a substitution salification reaction on thecompound of the formula 3 to obtain the compound erbtinib represented by formula 4. The preparation method of erbtinib can greatly shorten the production cycle when used for preparing erbtinib hydrochloride, can effectively avoid the defects of long production cycle, serious environmental pollution, unstable intermediate, difficult product purification, complex operation and the like, and has theadvantages of short reaction steps, simple operation, easy reaction, high product purity, high yield and low cost. The addition amount of reactants is properly controlled, the environmental requirements are clear, and a clear and new production direction is provided for process production.
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Paragraph 0009; 0036-0041

(2020/06/16)

Visible-light induced copper(i)-catalyzed oxidative cyclization of: O -aminobenzamides with methanol and ethanol via HAT
The use of the in situ generated ligand-copper superoxo complex absorbing light energy to activate the alpha C(sp3)-H of MeOH and EtOH via the hydrogen atom transfer (HAT) process for the synthesis of quinazolinones by oxidative cyclization of alcohols with o-aminobenzamide has been investigated. The synthetic utility of this protocol offers an efficient synthesis of a quinazolinone intermediate for erlotinb (anti-cancer agent) and 30 examples were reported.
Bhargava Reddy, Mandapati,Prasanth, Kesavan,Anandhan, Ramasamy
supporting information
p. 9601 - 9605
(2020/12/28)

Erlotinib derivative with killing performance on wild type lung cancer tumor cells and preparation method thereof
The invention discloses an erlotinib derivative with killing performance on wild cells and a preparation method thereof, and belongs to the technical field of medicine synthesis. According to the technical scheme, the erlotinib derivative is characterized in that the erlotinib derivative has a structure shown in the specification, wherein n is 1 or 2, n is 1 or 2, and R1 and R2 as well as R3 and R4 are different substituents. According to the invention, 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester is used as a raw material, and a series of erlotinib-1, 2, 3-triazole compounds with novel structures are obtained through six-step reaction; the compound has a good inhibition effect on IDO1, and a 1, 2, 3-triazole structure can form a relatively strong action effect with Fe ions in heme, sothat the enzyme activity of IDO1 is competitively inhibited; the compound has a good inhibition effect on wild lung cancer tumor cells, also has an inhibition effect on mutant lung cancer tumor cells, and has remarkable tumor cell inhibition activity universality by being compared with erlotinib.
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Paragraph 0031-0033

(2020/07/12)

Transition-metal and oxidant-free approach for the synthesis of diverse N-heterocycles by TMSCl activation of isocyanides
A highly efficient TMSCl-mediated addition of N-nucleophiles to isocyanides has been achieved. This transition-metal and oxidant-free strategy has been applied to the construction of various N-heterocyles such as quinazolinone, benzimidazole and benzothiazole derivatives by the use of distinct amino-based binucleophiles. The notable feature of this protocol includes its mild reaction condition, broad functional group tolerance and excellent yield. This journal is
Chen, Fen-Er,Dong, Lin,Li, Hongyan,Liu, Jinxin,Luo, Liangliang,Xiao, You-Cai,Zhou, Yuan
p. 29257 - 29262
(2020/10/02)

Preparation method of erlotinib hydrochloride intermediate
The invention provides a preparation method of an erlotinib hydrochloride intermediate. The preparation method comprises following steps: removing the methyl of vanillin, performing esterification, converting an aldehyde group into a nitrile group, and carrying out nitration, reduction, hydrolysis, and ring forming reactions. The reaction route is represented in the description. The technology isreasonable, the operation is simple, the cost is low, and the reaction yield is high.
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(2019/05/08)

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
p. 42 - 53
(2018/02/06)

A quinazoline derivative and its preparation method and application (by machine translation)
A quinazoline derivative, its synthesis is simple, raw material sources are extensive. It adopts the quinazoline skeleton, through the introduction of the fluorine-containing group - CF kuikui zuo lin link2 H或 - SCF3 , To obtain a series of with anti-tumor activity of the quinazoline derivatives, these compounds compared with erlotinib, demonstrates better activity, and less toxicity. A quinazoline derivative of the preparation method, by means of a simple substitution reaction can be obtained with high efficiency and high quality of the quinazoline derivatives, simple and convenient operation, high requirements on equipment, is suitable for use with large-scale production. An above-mentioned quinazoline derivatives, the quinazoline derivative can be applied to the production of anti-tumor drug, compared with the prior of for erlotinib, it can achieve a better curative effect and smaller toxic side effects. (by machine translation)
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Paragraph 0045-0049

(2019/01/14)

A convergent strategy towards febrifugine and related compounds
We report a modular five step synthetic route to the febrifugines that employs 2-(chloromethyl)allyl-trimethylsilane as a conjunctive reagent for the coupling of the piperidine and quinazolinone groups. We also demonstrate the application of a recent Rh-catalyzed quinazolinone synthesis for the facile generation of febrifugine analogs.
Maiden,Mbelesi,Procopiou,Swanson,Harrity
p. 4159 - 4169
(2018/06/12)

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
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Paragraph 0029-0041

(2018/03/01)

Method for preparing compound
The invention provides a method for preparing a compound as shown in a formula I which is described in the specification. The method comprises a step of contacting a compound as shown in a formula III which is described in the specification or a derivative thereof with a compound as shown in a formula II which is described in the specification so as to obtain the compound as shown in the formula I. In the formulas, R1 and R2 are hydrogen, alkoxy groups or heteroaromatic rings, preferably alkoxy groups; and R is hydrogen, an alkyl group, a phenyl group, a substituted phenyl group or a naphthyl group. The compound as shown in the formula I is a tinib drug intermediate 6,7-disubstituted quinazolinone. According to the method provided in embodiments in the invention, aldoketones are used as cyclization raw materials in replacement of carboxylic acids for preparation of tinib drug intermediate, and since the aldoketones are not corrosive, the method has low requirements on reaction equipment and is more favorable for industrial production.
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(2018/04/01)

Erlotinib preparation method
The invention relates to an erlotinib preparation method. The method for synthesizing erlotinib includes the steps: (1) reacting a compound 1 and paraformaldehyde under the condition of catalytic amount of boron trifluoride diethyl etherate to generate a compound 2; (2) reacting the compound 2 and ammonium hydroxide under the condition of catalytic amount of tetrabutylammonium bromide and ultrasound to generate a compound 3; (3) reacting the compound 3 and sulfoxide chloride to generate a compound 4; (4) reacting the compound 4 and aminophenylacetylene to generate erlotinib.
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(2017/10/22)

Intermediate for preparing erlotinib
The invention relates an intermediate for preparing an erlotinib. The intermediate is of a structure which is shown as the compound 2 in the description.
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Paragraph 0041; 0042; 0043; 0044; 0045

(2017/10/13)

Preparation method of erlotinib intermediate
The invention relates to a preparation method of an erlotinib intermediate. The preparation method concretely comprises the following steps: implanting a synthesis route described in the description; adding a compound 2 into ammonia water, adding a catalytic amount of tetrabutyl ammonium bromide at the room temperature, and carrying out ultrasonic treatment for 5-30min to generate a compound 3, wherein the ultrasonic frequency is 30-50kHz.
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Paragraph 0041; 0042; 0043; 0044; 0045

(2017/09/01)

The preparation method of the AKT
The invention discloses a preparation method of erlotinib and belongs to the technical field of medicament preparation. In the preparation method, 4,5-di(2-methoxylethoxy)-2-nitrobenzonitrile is used as a raw material and is subjected to reduction and hydrolysis to obtain an intermediate namely 2-amino-4,5-di(2-methoxylethoxy) benzamide which is subjected to cyclization with triethyl orthoformate directly to obtain an erlotinib key intermediate namely 6,7-di(2-methoxylethoxy)-3H-quinazoline-4-one, and a chlorinated product of quinazoline reacts with aminophenylacetylene to obtain erlotinib. By adopting the preparation method disclosed by the invention, the defects that an expensive catalyst is used by nitryl reduction in the conventional synthetic method and the temperature during cyclization is relatively high are overcome, a process with a formamidine intermediate is also avoided, the reaction step is shortened, the reaction cost is reduced, and the yield is improved. Moreover, all reaction conditions in the preparation method are very mild, so that the preparation method is particularly suitable for industrial production.
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Paragraph 0030-0031; 0035-0036

(2017/10/28)

Method for synthesizing Erlotinib
The invention discloses a method for synthesizing Erlotinib. The method comprises the steps of adding 2-amino-4,5-di(2-methoxyethoxy)benzamide, methanol and a catalyst iridium complex into a microwave reaction vessel, carrying out a reaction for a plurality of hours at the temperature of 130+/-10 DEG C, cooling the reacted material to room temperature, carrying out spin-drying on the solvent, then, carrying out column separation so as to obtain 6,7-di(2-methoxyethoxy)quinazoline, then, carrying out a chlorination reaction under the participation of phosphorus oxychloride so as to produce 4-chloro-6,7-di(2-methoxy ethoxy)quinazoline, and then, carrying out an amination reaction, thereby obtaining the Erlotinib. According to the method, the non-toxic and renewable methanol is adopted as a raw material during reaction, and byproducts, i.e., hydrogen gas and water are produced during the reaction, so that the method is free of environmental pollution and meets the requirements of green chemistry, thereby having a broad development prospect.
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Paragraph 0011; 0014

(2018/03/13)

Antirust B erlotinid hydrochloride method for the synthesis of
The invention discloses a synthetic method applicable to industrial production of an erlotinib hydrochloride B-type crystal. According to the method, 2-amino-4,5-di-(2-methoxyethoxy)-ethyl benzoate hydrochloride is used as a raw material, ring closure is carried out so as to obtain 6,7-di-(2-methoxyethoxy)-3,4-dihydroquinazoline-4-one, then chlorination is directly carried out so as to obtain a product which reacts with 3-aminophenylacetylene in an methanol-water mixed solvent, and cooling and crystallization are carried out after completion of the reaction so as to obtain the finished erlotinib hydrochloride B-type crystal. Compared with the prior art, the invention has the following advantages: the synthetic method is easy and practicable to operate and does not need crystal phase transformation, and the prepared erlotinib hydrochloride B-type crystal has a single and stable crystal form and high purity and is suitable for large-scale industrial production.
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Paragraph 0039-0040

(2017/01/19)

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.
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Paragraph 0067; 0068

(2016/11/09)

Preparation method of erlotinib intermediate
The invention relates to a preparation method of an erlotinib intermediate. The method concretely comprises the following steps: 1, dissolving vanillin in an organic solvent I, adding aluminum trichloride, adding pyridine in a dropwise manner, and reacting to obtain ELTA; 2, dissolving the ELTA in an organic solvent II, adding 2-chloroethylmethyl ether, potassium carbonate and a phase transfer catalyst, and reacting to obtain ELTB; 3, adding the ELTB to water, adding an alkali and potassium permanganate, and reacting to obtain ELTC; 4, adding concentrated sulfuric acid to methanol in a dropwise manner, adding the ELTC to the above reaction system, and reacting to obtain ELTD; 5, adding concentrated sulfuric acid to concentrated nitric acid in a dropwise manner, dissolving the ELTD in an organic solvent IV, adding a prepared mixed acid to the reaction system, and reacting to obtain ELTE; 6, adding the ELTE, iron powder and ammonium chloride to an organic solvent V, adding concentrated hydrochloric acid in a dropwise manner, and reacting to obtain ELTF; and 7, adding the ELTF, trimethyl orthoformate and ammonium acetate to an organic solvent VI, and reacting to obtain the erlotinib intermediate.
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(2016/10/10)

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.
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Paragraph 0115; 0116; 0117

(2016/10/07)

Acceptorless Dehydrogenative Coupling of o-Aminobenzamides with the Activation of Methanol as a C1 Source for the Construction of Quinazolinones
A strategy for the synthesis of quinazolinones via acceptorless coupling of o-aminobenzamides with methanol has been accomplished in the presence of the metal-ligand bifunctional catalyst [Cp?Ir(2,2′-bpyO)(H2O)]. Notably, this research exhibited the potential of transition-metal-catalyzed activation of methanol as a C1 source for the construction of heterocycles.
Li, Feng,Lu, Lei,Liu, Pengcheng
supporting information
p. 2580 - 2583
(2016/06/15)

A Mild and Regioselective Route to Functionalized Quinazolines
A Rh-catalyzed ortho-amidation cyclocondensation sequence gave a range of 4-aminoquinazolines in high yield. The method features a remarkably mild C(sp2)-H activation step and can be exploited to rapidly access compounds with established biological activity.
Maiden, Tracy M. M.,Swanson, Stephen,Procopiou, Panayiotis A.,Harrity, Joseph P. A.
p. 14342 - 14346
(2015/10/05)

Facile and efficient oxidation of quinazolines into quinazolin-4(3 H)-ones by peracetic acid
A new approach to synthesize quinazoline-4(3H)-ones was achieved by oxidation of quinazolines using peracetic acid, which possesses some advantages of economic reagents, simplified operation, high efficiency, and environmental friendliness. Application of this method allowed us to synthesize a series of quinazolin-4(3H)-ones with different substituents at 6 and 7 positions in good to excellent yields, including the key intermediates of tyrosine kinase inhibitors such as PD153035, Erlotinib, and Gefitinib. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]
Jin, Jian-Wen,Zhang, Lin,Meng, Guang-Rong,Zhu, Jian-Hua,Zhang, Qian
p. 346 - 351
(2014/01/06)

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)

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)

FUSED QUINAZOLINE DERIVATIVES AND USES THEREOF
Fused quinazoline derivatives and uses thereof as protein tyrosine kinase inhibitors and aurora kinase inhibitors are disclosed. Said protein tyrosine kinase inhibitors and aurora kinase inhibitors can be used in treating cancers, leukaemia and the diseases relevant to differentiation and proliferation. Said protein tyrosine kinase and aurora kinase dual inhibitors are the compounds represented by the following general formula or salts thereof.
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(2013/05/23)

AN IMPROVED PROCESS FOR THE PREPARATION OF ERLOTINIB HYDROCHLORIDE FORM A
The present invention relates to an improved process for the preparation of Erlotinib hydrochloride pure Form A. The present invention also provides a pharmaceutical composition using the erlotinib hydrochloride pure Form A of the invention.
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Page/Page column 12; 13

(2013/11/05)

Design, synthesis of novel quinazolone alkaloids derivatives as potential antitumor agents
Several novel quinazolone alkaloids derivatives were synthesized. Some of the target compounds were determined against human prostate cancer DU145 and pancreatic cancer Miacapa2 cells in vitro. The entire compounds had been identified by 1HNMR, 13CNMR, IR, MS and EA.
Zheng, Youguang,Sun, Min,Liu, Yi,Li, Mingdong,Ji, Min
scheme or table
p. 295 - 300
(2012/06/01)

POLYCYCLIC QUINAZOLINES, PREPARATION THEREOF, AND USE THEREOF
At least one active pharmaceutical ingredient is chosen from polycyclic quinazolines of formula V, pharmaceutically acceptable salts thereof, and hydrates of the pharmaceutically acceptable salts. The active pharmaceutical ingredients disclosed may be inhibitors of protein tyrosine kinase inhibitors and/or aurora kinase. The active pharmaceutical ingredients can be used for treating cancers susceptible to treatment with protein tyrosine kinase inhibitors and/or aurora kinase inhibitors.
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(2011/12/12)

PREPARATION PROCESS OF ERLOTINIB
Preparation process of erlotinib or its salts comprising: reacting 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline with 3-ethynylaniline or a salt thereof in the presence of a base and a reaction-inert solvent, and optionally, treating the compound obtained with a pharmaceutically acceptable acid to form the corresponding pharmaceutically acceptable salt. The compound 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline can be prepared either from 4-methoxyquinazoline-6,7-diol or 6,7-bis(2-methoxyethoxy)quinazolinone. The compounds 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline and 4-methoxyquinazoline-6,7-diol are new intermediates useful for the preparation of erlotinib or its salts.
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Page/Page column 19

(2011/07/09)

Preparation process of erlotinib
Preparation process of erlotinib or its salts comprising: reacting 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline with 3-ethynylaniline or a salt thereof in the presence of a base and a reaction-inert solvent, and optionally, treating the compound obtained with a pharmaceutically acceptable acid to form the corresponding pharmaceutically acceptable salt. The compound 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline can be prepared either from 4-methoxyquinazoline-6,7-diol or 6,7-bis(2-methoxyethoxy)quinazolinone. The compounds 6,7-bis(2-methoxyethoxy)-4-methoxyquinazoline and 4-methoxyquinazoline-6,7-diol are new intermediates useful for the preparation of erlotinib or its salts.
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Page/Page column 11

(2011/08/07)

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)

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.
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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.
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Page/Page column 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)

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
p. 39 - 48
(2008/02/02)

Synthesis and biological evaluation of allenic quinazolines using palladium-catalyzed hydride-transfer reaction
Allenic quinazolines 13a-h were designed as mimics of Tarceva, which is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and synthesized from the corresponding 4-(iodoanilino)quinazolines or 4-(iodophenoxy)quinazolines with N,N-dicyclohexylprop-2-ynylamine by the Sonogashira coupling followed by palladium-catalyzed hydride-transfer reaction. Cell growth inhibition of 13a-h toward A431, Kato III, SKBR3, and HepG2 was examined. Among the compounds synthesized, 13a showed a similar cell growth inhibition to Tarceva. Moreover, 13d and 13h exhibited a specific growth inhibition toward Kato III cells (IC50 = 12 and 4.7 μM, respectively), although a significant inhibition toward other three cell lines was not observed at a 100 μM concentration of compounds.
Nakamura, Hiroyuki,Onagi, Shinya
p. 2539 - 2542
(2007/10/03)

SUBSTITUTED 4-(INDOL-3-YL)QUINAZOLINES AND THEIR USE
The invention relates to the use of substituted 4-(indol-3-yl)quinazolines or one of their salts for inhibiting proteinase activity, in particular the EGF receptor-specific tyrosine protein kinase, for treating tumours, osteoporosis or proliferative epidermal diseases, in addition to novel substituted 4-(indol-3-yl)quinazolines or one of their salts and to a method for producing said substances. The invention also relates to the use of substituted 4-(indol-3- yl)quinazoline derivatives or one of their salts for inhibiting protein kinase activity, in particular for crop protection in the development of fungicidal, herbicidal or insecticidal active ingredients.
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(2008/06/13)

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)

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.
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(2008/06/13)

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)

PROCESS FOR PRODUCING QUINAZOLIN-4-ONE DERIVATIVE
A process for producing a quinazolin-4-one compound having the formula: [wherein R1, R2, R3 and R4 each represents a group not participating in the below-mentioned reaction, and R1, R2, R3 and R4 can be combined together to form a ring] which comprises reacting an anthranilic acid derivative having the formula: [wherein R5 is a hydrogen atom or a hydrocarbyl group] with a formic acid derivative in the presence of an ammonium carboxylate.
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(2008/06/13)

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.
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(2008/06/13)