cas 380843-75-4, Bosutinib | Articles data

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A robust, streamlined approach to bosutinib monohydrate
This article describes a systematic approach used to streamline the process for the isolation of bosutinib monohydrate, a promiscuous solvate former. A thorough understanding of the complex solid form landscape was garnered, and this knowledge was used to
Withbroe, Gregory J,Seadeek, Chris,Girard, Kevin P,Guinness, Steven M,Vanderplas, Brian C,Vaidyanathan, Rajappa
p. 500 - 504
(2013)
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Preparation method of bosutinib
The invention provides a preparation method of bosutinib. The method comprises the following steps: under the protection of inert gas, adding SM-1 and alkaline salt into an organic solvent, dropwise adding phosphorus oxychloride at a controlled temperature, cooling a reaction solution to room temperature after a reflux reaction is finished, filtering, dissolving an obtained filter cake into a mixed solvent, filtering again, adding an organic alkali into a filtrate, stirring for crystallization, filtering, and carrying out vacuum drying on the filter cake to obtain the target product bosutinib.Compared with the prior art, the synthesis method for preparing bosutinib by adding the alkaline salt into the reaction system is mild in reaction condition, high in material solubility, short in reaction time, capable of effectively shortening the production period and suitable for industrial scale-up production.
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Paragraph 0053-0082

(2020/09/21)

Method for preparing bosutinib intermediate
The invention provides a method for preparing a bosutinib intermediate. The method comprises the following steps: A, adding SM-1, 1-bromo-3-chloropropane and an acid-binding agent into a reaction solvent, controlling the temperature until the reaction is
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Paragraph 0041-0078

(2020/09/20)

Bosutinib compound and preparation method thereof
The invention provides a novel bosutinib impurity (I) and a preparation method thereof. The impurity serves as a reference standard or reference and can be used for quality control in raw materials and/or preparations of bosutinib. The invention further p
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Paragraph 0082-0087

(2019/11/12)

Bosutinib purification method
The invention provides a bosutinib purification method. The method includes the steps of firstly, dissolving crude bosutinib in an acetonitrile-water mixed solvent; secondly, optionally performing activated carbon decoloring, and filtering to obtain filtrate; thirdly, cooling, crystallizing, filtering, and drying to obtain purified bosutinib. The bosutinib purification method has the advantages that the method can replace a column chromatography purification method or a preparative chromatography purification method to remove impurities, which is hard to purify by a conventional crystallizingmethod, in the crude bosutinib, and the method is low in solvent use amount, simple in process, high in purification yield and product purity and beneficial to industrial production.
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(2019/10/22)

Preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and preparation method of bosutinib
The invention provides a preparation method of a disubstituted 4-chloroquinoline-3-carbonitrile derivative and a preparation method of bosutinib. The preparation method of the disubstituted 4-chloroquinoline-3-carbonitrile derivative comprises the following steps: disubstituted o-nitrobenzoate (II) used as a raw material and acetonitrile are condensed under the action of an alkali to obtain a compound of formula III; the compound of formula III and a chloroformylating reagent undergo a chloroformylating reaction to obtain a compound of formula IV1 or formula IV2; and the compound of formula IV1 undergoes catalytic hydrogenation cyclization in the presence of a hydrogenation catalyst to prepare 7-[3-(4-methyl-1-piperazinyl)propoxy]-6-methoxy-4-chloroquinoline-3-carbonitrile (Ia), or the compound of formula IV2 is subjected to catalytic hydrogenation cyclization and anhydride amidation to prepare 6-acetamido-7-ethoxy-4-chloroquinolin-3-carbonitrile (Ib). The compound of formula Ia or Ibis used to prepare bosutinib, neratinib or pelitinib. The method of the invention has the advantages of short process flow, simplicity in operation, easiness in realization, low cost, few three wastes, high yield, high purity, and easiness in industrial production.
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(2019/10/01)

Purification method of bosutinib
The invention provides a purification method of bosutinib. The purification method comprises the following steps: (1) dissolving a crude product of a compound of a formula I into a solvent A, and reacting with a benzoic acid solution containing benzoic acid and a solvent B, so as to obtain a compound of a formula II; (2) optionally, dissolving the compound of the formula II obtained in the step (1) into a solvent C, and reacting with a benzoic acid solution containing benzoic acid and a solvent D, so as to obtain the compound of the formula II; and (3) hydrolyzing the compound by the formula II obtained in the step (1) or the step (2) in the presence of alkali, water and other optional solvents, so as to obtain a pure product of the compound of the formula I. The purification method has the beneficial effects that a column chromatography manner or a preparative chromatography purification manner is not adopted, and impurities with potential genotoxicity which are unlikely to be removedin a manner that the column chromatography or the preparative chromatography purification manner is not adopted and a conventional crystallization method is directly adopted can be substantially reduced; and the amount of the adopted solvent is small, the after-treatment is convenient, the purification yield and the product purity are relatively high, and the method is applicable to industrial production.
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Paragraph 0075-0076

(2018/07/30)

AMORPHOUS FORM OF BOSUTINIB
The present invention provides an amorphous form of bosutinib, a process for its preparation, its pharmaceutical composition, and a method of use thereof.
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Page/Page column 5-6

(2017/03/21)

NOVEL CRYSTALLINE POLYMORPHS OF 4-[(2.4-DICHIORO-5-METHOXVPHENVL)ANIINOL- 6-METHOXV-7-13-(4-METHYL-L-PIPERAZINVL)PROPOXVL-3-QUINOLINECARBONITRILE AND PROCESS FOR PREPARATION THEREOF
The present invention relates to novel crystalline polymorphs of 4-[(2,4-dichloro-5- methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-quinoline carbonitrile represented by the following structural formula- 1 and process for preparation thereof.
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Page/Page column 10-11

(2017/09/02)

New Synthetic Process for Bosutinib
A new and improved synthetic route to bosutinib is described on a hectogram scale. The key step is the intramolecular cyclization of a 3-(2-aminophenyl)-3-oxopropanenitrile with N,N-dimethylformamide dimethyl acetal to form the 3-cyano-4-hydroxyquinoline ring of 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile. A practical synthetic method to 2,4-dichloro-5-methoxyaniline is also established. Bosutinib is obtained in 18.0% yield over nine steps from acetovanillone with 98.9% purity (HPLC).
Mao, Yongjun,Zhu, Chunping,Kong, Ziyang,Wang, Jiao,Zhu, Guoqing,Ren, Xinfeng
p. 3133 - 3138
(2015/10/19)

BOSUTINIB FORMS AND PREPARATION METHODS THEREOF
The present subject matter relates to solvates and the amorphous form of bosutinib; the solvates namely being a propylene glycol solvate and an acetonitrile solvate. Also provided are processes for preparing the propylene glycol solvate, the amorphous form and the crystalline acetonitrile solvate of bosutinib; as well as compositions comprising said forms. Bosutinib is a 3-quinolinecarbonitrile kinase inhibitor and is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ chronic myelogenous leukemia (CMS) with resistance or intolerance to prior therapy.
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Page/Page column 25

(2015/09/28)

PROCESS FOR PREPARATION OF BOSUTINIB
The present invention relates to a process for the preparation of compound of Formula (I). The present invention further relates to novel intermediates useful in the preparation of Bosutinib. The present invention also relates to a process for the preparation of novel Bosutinib intermediates.
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(2016/04/19)

A practical synthesis of 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, a key intermediate to bosutinib
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Mao, Yongjun,Tian, Xin,Jiang, Luobin,Zhu, Guoqing,Wang, Han
p. 207 - 213
(2015/05/27)

A new and practical synthesis of bosutinib
New and improved synthetic route of bosutinib is described on a decagram scale. An intramolecular cyclization of 3-amino-2-(2-bromobenzoyl)-acrylonitrile (22) in K2CO3/DMF condition to form the key 3-cyano-4-hydroxyquinoline intermediate (13) is adopted as the key step. Bosutinib is obtained in 13.7% yield over ten steps and 98.9% purity (HPLC), which make it as a process of cost effective, environmentally friendly and feasible for scale-up operation.
Wang, Han,Zhu, Chunping,Zhu, Guoqing,Tian, Xin,Shen, Yongjia,Mao, Yongjun
p. 2806 - 2813
(2015/02/19)

Synthesis of bosutinib from 3-methoxy-4-hydroxybenzoic acid
This paper reports a novel synthesis of bosutinib starting from 3-methoxy-4-hydroxybenzoic acid. The process starts with esterification of the starting material, followed by alkylation, 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 the compounds were determined by HPLC.
Yin, Xiao Jia,Xu, Guan Hong,Sun, Xu,Peng, Yan,Ji, Xing,Jiang, Ke,Li, Fei
experimental part
p. 4261 - 4266
(2010/09/18)

TREATMENT OF IMATINIB RESISTANT LEUKEMIA
The present invention provides 4-anilino-3-quinolinecarbonitriles compounds useful for treating a subject having an BcrAbl positive leukemia that is resistant to imatinib.
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(2009/01/24)

4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (CML)
Compounds of the formula: wherein: n is an integer from 1-3; X is N, CH, provided that when X is N, n is 2 or 3; R is alkyl of 1 to 3 carbon atoms; R1 is 2,4-diCl, 5-OMe; 2,4-diCl; 3,4,5-tri-OMe; 2-Cl, 5-OMe; 2-Me, 5-OMe; 2,4-di-Me; 2,4-diMe-5-OMe, 2,4-diCl, 5-OEt; R2 is alkyl of 1 to 2 carbon atoms, and pharmaceutically acceptable salts thereof.
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Page/Page column 5

(2008/06/13)

4-ANILINO-3-QUINOLINECARBONITRILES FOR THE TREATMENT OF CHRONIC MYELOGENOUS LEUKEMIA (CML)
Compounds of the formula (I): wherein: n is an integer from 0-3; X is N, CH; R is alkyl of 1 to 3 carbon atoms; R' is 2,4-diCl, 5-OMe in para, ortho, or meta position; 2,4-diCl in para position; 3,4,5-tri-OMe in para position; 2-Cl, 5-OMe in para position
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Page/Page column 26

(2010/02/11)

7-Alkoxy-4-phenylamino-3-quinolinecarbonitriles as Dual Inhibitors of Src and Abl Kinases
We previously reported that several 7-alkoxy-4-phenylamino-3-quinolinecarbonitriles were potent inhibitors of Src kinase activity. We disclose here a new highly efficient and versatile route to these compounds, which are also potent inhibitors of Abl kina
Boschelli, Diane H.,Wang, Yanong D.,Johnson, Steve,Wu, Biqi,Ye, Fei,Barrios Sosa, Ana Carolina,Golas, Jennifer M.,Boschelli, Frank
p. 1599 - 1601
(2007/10/03)

Process for the preparation of 7-substituted-3 quinolinecarbonitriles
There is provided a process for the preparation of 7-substituted-3-quinolinecarbonitriles and intermediates useful in a process to prepare 7-substituted-3-quinolinecarbonitriles and pharmaceutically acceptable salts is described. Where 7-fluoro-4-oxo-1,4-
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Page/Page column 24

(2010/11/30)

Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity
Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino] -6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC50 = 30 nM) several additional analogues were prepared. Optimization of the C-4 anilino group of la led to lc which contains a 2,4-dichloro-5-methoxy- substituted aniline. Replacement of the methoxy group at C-7 of 1c with a 3-(morpholin-4-yl)propoxy group provided 2c resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c with other trisubstituted anilines at C-4 were also potent Src inhibitors and the propoxy group of 2c was preferred over ethoxy butoxy or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a which had an IC50 of 1.2 nM in the Src enzymatic assay an IC50 of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a which had higher 1 and 4 h plasma levels than 2c effectively inhibited tumor growth in xenograft models.
Boschelli,Ye,Wang,Dutia,Johnson,Wu,Miller,Powell,Yaczko,Young,Tischler,Arndt,Discafani,Etienne,Gibbons,Grod,Lucas,Weber,Boschelli
p. 3965 - 3977
(2007/10/03)