cas 152459-95-5, Imatinib | Articles data

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Preparation of copper(II) oxide bound on polystyrene beads and its application in the aryl aminations: Synthesis of Imatinib
CuO nanoflakes bound on polystyrene beads (PS-CuO) were prepared through the oxidation of copper(I) bromide in a suspension of polystyrene. The use of PS-CuO as a catalyst in the presence of KOtBu in the coupling reactions of aryl bromides and amines afforded the coupled products with a yield range of 15-89%. This catalytic system also afforded the key fragment in good yield for the synthesis of Imatinib (Gleevec).
Heo, Yumi,Hyun, Dajung,Kumar, Manian Rajesh,Jung, Hyun Min,Lee, Sunwoo
p. 6657 - 6661
(2012)
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Microwave-assisted solid phase synthesis of Imatinib, a blockbuster anticancer drug
An expeditious, high yield and convenient synthesis of Imatinib was carried out on an aldehydic, super acid-sensitive resin, through an efficient, microwave-assisted synthetic protocol. The high versatility of the reaction scheme may enable the straightforward preparation of libraries of potential protein kinase inhibitors endowed with large molecular diversity.
Leonetti, Francesco,Capaldi, Carmelida,Carotti, Angelo
p. 3455 - 3458
(2007)
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Synthesis of imatinib: A convergent approach revisited
A classical convergent approach for the synthesis of the anticancer drug imatinib has been substantially improved. Imatinib was assembled by coupling the amine and carboxylic acid precursors by using N,N′-carbonyldiimidazole (CDI) as a condensing agent. Both intermediates have been synthesized by novel efficient methods.
Ivanov, Andrey S.,Shishkov, Sergey V.
p. 619 - 623
(2009)
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A PROCESS FOR PREPARATION OF IMATINIB BY USING VILSMEIER REAGENT
The present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent preferably under basic condition. Vilsmeier reagent in the present invention is prepared by reaction of chlorinating agent and catalyst. In a preferred embodiment Chlorinating agent is thionyl chloride and catalyst is dimethyl formamide.
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Page/Page column 10; 13-15

(2021/07/17)

SYNTHESIS OF 6-METHYL-N1-(4-(PYRIDIN-3-YL)PYRIMIDIN-2-YL)BENZENE-1,3-DIAMINE
Processes and useful intermediates for the synthesis of the tyrosine kinase inhibitors Formula (II) nilotinib and Formula (IV) imatinib. Key intermediates, method for their synthesis and their use in a divergent synthesis, making use of a Curtius rearrangement, to nilotinib and imatinib are described.
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(2021/04/23)

Synthesis of imatinib, a tyrosine kinase inhibitor, labeled with carbon-14
Imatinib (Gleevec) is a multiple tyrosine kinase inhibitor that decreases the activity of the fusion oncogene called BCR-ABL (breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog) and is clinically used for the treatment of chronic myelogenous leukemia and acute lymphocytic leukemia. Small molecule drugs, such as imatinib, can bind to several cellular proteins including the target proteins in the cells, inducing undesirable effects along with the effects against the disease. In this study, we report the synthetic optimization for 14C-labeling and radiosynthesis of [14C]imatinib to analyze binding with cellular proteins using accelerator mass spectroscopy. 14C-labeling of imatinib was performed by the synthesis of 14C-labeld 2-aminopyrimidine intermediate using [14C]guanidine·HCl, which includes an in situ reduction of an inseparable byproduct for easy purification by HPLC, followed by a cross-coupling reaction with aryl bromide precursor. The radiosynthesis of [14C]imatinib (specific activity, 631 MBq/mmol; radiochemical purity, 99.6%) was achieved in six steps with a total chemical yield of 29.2%.
Kang, Julie,Lee, Jun Young,Park, Jeong-Hoon,Chang, Dong-Jo
p. 174 - 182
(2020/02/13)

Preparation method of imatinib mesylate
The invention discloses a preparation method of imatinib mesylate. The method comprises the following steps: chlorinating imatinib acid[4-(4-methylpiperazine-1-ylmethyl)benzoic acid dihydrochloride] with thionyl chloride to generate an imatinib mesylate intermediate I; condensing the imatinib mesylate intermediate I with imatinib amine [N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine] toobtain an imatinib mesylate intermediate II, and finally salifying the imatinib mesylate intermediate II with methanesulfonic acid to obtain imatinib mesylate. According to the invention, the raw materials imatinib acid and imatinib amine used in the method are common medical intermediates, other raw materials and reagents used in the process are convenient and easy to obtain, the reaction process and post-treatment operation are simple and convenient, the yield is high, and the production cost is effectively reduced through process optimization.
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Paragraph 0009

(2020/12/05)

Synthesis method of imatinib free base (by machine translation)
The invention relates to a synthetic method of imatinib free base. [N - (5 - amino -2 - methylphenyl) -4 - (pyridin -3 -yl) pyrimidine -2 - amine and 1 - [(4 - bromophenyl) methyl] -4 - methylpiperazine are used as raw materials to generate imatinib under the catalysis of palladium acetate and ligand 4,5 - bis (triphenylphosphine -9, 9 -dimethylxanthene) in 1 atm carbon monoxide atmosphere. The synthetic route of the invention is simple and effective, avoids the use of highly contaminated reagents such as thionyl chloride or phosphorus oxychloride, and has the advantages of cheap and easily available starting materials and wide market supply. The method is simple to operate. The method is mild in process condition, low in pollution and suitable for industrial production. (by machine translation)
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Paragraph 0033; 0041-0048

(2021/01/04)

Synthesis method of imatinib and imatinib mesylate
The invention relates to a synthesis method of imatinib and imatinib mesylate. The method comprises the following steps: condensing 3-acetylpyridine and N,N-dimethylformamide dimethyl acetal which aretaken as initial raw materials to obtain 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, then reacting with 2-methyl-5-nitrophenylguanidine nitrate to form a pyrimidine ring, performing nitro reductionto obtain N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine, amidating the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine and 4-(chloromethyl)benzoyl chloride, performing affinitysubstitution with 1-methylpiperazine to obtain imatinib, and salifying the imatinib and methanesulfonic acid. The products obtained by the method have the advantages of few impurities, simplicity in post-treatment, high total yield, greenness, environmental protection and safety, and is suitable for a production process for large-scale industrial production of imatinib mesylate.
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(2020/05/02)

Modular Continuous Flow Synthesis of Imatinib and Analogues
A modular continuous flow synthesis of imatinib and analogues is reported. Structurally diverse imatinib analogues are rapidly generated using three readily available building blocks via a flow hydration/chemoselective C-N coupling sequence. The newly developed continuous flow hydration and amidation modules each exhibit a broad scope with good to excellent yields. Overall, the method described does not require solvent switches, in-line purifications, or packed-bed apparatuses due to the judicious manipulation of flow setups and solvent mixtures.
Fu, Wai Chung,Jamison, Timothy F.
supporting information
p. 6112 - 6116
(2019/08/26)

One-pot propagation of (Hetero)Arylamines: Modular synthesis of diverse Amino-di(hetero)arylamines
Formal propagation of (hetero)arylamine is achieved via a one-pot Buchwald–Hartwig C–N cross-coupling and nitro reduction sequence, enabling a rapid modular synthesis of diverse amino-di(hetero)arylamines from (hetero)arylamines and halogenated nitrobenzenes. Various functionalized aromatic amines with different electronic and steric environments can be efficiently prolongated to formally incorporate another arylamino fragments. This approach has been successfully applied in the synthesis of more than forty amino-di(hetero)arylamines. The applicability of this method has also been demonstrated in the synthesis of oligoanilines and the tyrosine-kinase inhibitor Imatinib.
Liang, Xueting,Xu, Liang,Li, Cuihua,Jia, Xin,Wei, Yu
p. 721 - 731
(2019/01/08)

Synthesis of Imatinib by C-N Coupling Reaction of Primary Amide and Bromo-Substituted Pyrimidine Amine
A new method for imatinib synthesis is described by using the C-N coupling reaction of 4-(4-methylpiperazine-1-methyl)benzamide with N-(5-bromo-2-tolyl)-4-(3-pyridyl)pyrimidin-2-amine to form imatinib. In this synthetic route, the high efficiency and high selectivity of nano-ZnO as a catalyst is key to the mild hydrolysis of 4-(4-methylpiperazine-1-methyl)benzonitrile into the corresponding amide. The total imatinib yield was 51.3%, and the purity was 99.9%. This simple and effective synthetic pathway avoids gene-impurity production (as classified by the FDA Center for Drug Evaluation and Research), and the synthesis is environmentally friendly with a short reaction time.
Wang, Cuiling,Bai, Xiao,Wang, Rui,Zheng, Xudong,Ma, Xiumei,Chen, Huan,Ai, Yun,Bai, Yajun,Liu, Yifeng
p. 1918 - 1925
(2019/09/07)

Synthesis method of imatinib
The invention discloses a synthesis method of imatinib and belongs to the field of synthesis of medical intermediates. The method comprises the following steps: taking N-(5-amino-2-methylphenyl)-4-(3-pyridine)-2-pyrilamine as a raw material, carrying out silanization reaction, then enabling the raw material to carry out condensation reaction with 4-[(4-methyl-1-piperazine)methyl]dihydrochloride benzoate in the presence of alkali and a catalyst in N,N'-carbonyl diimidazole to obtain the imatinib. The synthesis method of imatinib is high in yield and simple to operate, and is suitable for industrial production; the product is easy to purify, high in quality and high in purity.
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Paragraph 0015; 0016; 0028; 0033; 0036; 0037

(2018/11/22)

Method for preparing high-purity imatinib
The invention discloses a method for preparing high-purity imatinib, and belongs to the field of synthesis of medical intermediates. According to the method, N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-2-pyrimidinamine is used as a raw material; the raw material reacts with trimethyl halosilane in presence of alkali, so that an amino protective intermediate is obtained; the imatinib is obtained byenabling the obtained amino protective intermediate and N, N'-carbonyl diimidazole to be subjected to a condensation reaction together with 4-[(4-methyl-1-piperazine) methyl] benzoic acid dihydrochloride in presence of alkali and a catalyst. The product prepared by the method is easy to purify, high in purify and simple to operate, thus being suitable for industrial production.
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Paragraph 0028; 0031; 0032; 0033

(2018/12/02)

Imatinib synthesis method
The invention discloses an imatinib synthesis method, and relates to the technical field of production of western medicines. A unique selenium-promoting large specific surface area selenium and nitrogen hybrid carbon nanofiber loaded copper catalyst is adopted to catalyze the key coupling step in the synthesis of imatinib, an imatinib product with a higher yield is obtained, and the metal residueis low. In addition, by using the catalyst, no alkali is used in the coupling reaction, and released hydrogen bromide and the product form a stable salt. The free imatinib is obtained through the alkali treatment. In addition, the catalyst can also be recycled for multiple times. The method is clean and environmentally friendly, is high in yield, is good in product quality, is low in cost, and hasa very high practical value.
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Paragraph 0015-0019; 0032

(2018/07/07)

Spectroscopic Studies of the Chan-Lam Amination: A Mechanism-Inspired Solution to Boronic Ester Reactivity
We report an investigation of the Chan-Lam amination reaction. A combination of spectroscopy, computational modeling, and crystallography has identified the structures of key intermediates and allowed a complete mechanistic description to be presented, including off-cycle inhibitory processes, the source of amine and organoboron reactivity issues, and the origin of competing oxidation/protodeboronation side reactions. Identification of key mechanistic events has allowed the development of a simple solution to these issues: manipulating Cu(I) → Cu(II) oxidation and exploiting three synergistic roles of boric acid has allowed the development of a general catalytic Chan-Lam amination, overcoming long-standing and unsolved amine and organoboron limitations of this valuable transformation.
Vantourout, Julien C.,Miras, Haralampos N.,Isidro-Llobet, Albert,Sproules, Stephen,Watson, Allan J. B.
p. 4769 - 4779
(2017/04/11)

N-phenyl-2-pyrimidine-amine derivatives
The present invention relates to novel amides and a process for preparing these amides.
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(2017/03/14)

Preparation method for imatinib
The invention discloses a preparation method for imatinib. According to the method, N-(5-iodo-2-methylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine and 4-((4-methyl-piperazin-1-yl)methyl)benzamide are used as raw materials; potassium phosphate, 1,10-phenanthroline and cuprous iodide are added; a reaction at room temperature is carried out; and aftertreatment is carried out so as to obtain imatinib. The method provided by the invention overcomes the problems of wearing of equipment and high energy consumption due to a high-temperature long-time reaction and is mild in reaction conditions, easy to operate, high in yield and suitable for industrial scale-up production.
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Paragraph 0029; 0041; 0042; 0043; 0044

(2017/07/21)

Preparation method of imatinib mesylate
The invention discloses a preparation method of imatinib mesylate. The method specifically comprises steps as follows: 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride type compounds II are taken as a starting material, sodium carbonate and N, N'-carbonyl diimidazole are added, acyl imidazole with higher activity is obtained, separation is not required, N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine type compounds IV and a catalyst imidazole hydrochloride are directly added, the mixture reacts, free alkali imatinib is obtained, methylsulfonic acid is added for salt formation, and imatinib mesylate in an alpha crystal form is obtained after recrystallization. The preparation method has the advantages of being mild in reaction condition, lower in cost, simple and convenient to operate, high in yield, good in reaction reproducibility, economical, environment-friendly and suitable for industrial production and producing fewer side reactions.
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Paragraph 0035; 0036; 0037; 0038; 0039; 0030-0050

(2017/07/20)

Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives
In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-one derivative, exhibited an IC50 value comparable to that of the drug imatinib against c-Src kinase, and another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated an IC50 value of 8.39 μM. Furthermore, the constitution of the cyclic amide derivative was confirmed by the single-crystal X-ray diffraction technique. These results may serve as a gateway for developing novel next-generation kinase inhibitors.
Manchanda, Priyanka,Parshad, Badri,Kumar, Amit,Tiwari, Rakesh K.,Shirazi, Amir N.,Parang, Keykavous,Sharma, Sunil K.
(2017/04/11)

Purification method of imatinib
The invention relates to a purification method of imatinib. The method has the characteristics of simple technique, high safety, environment friendliness, low cost and favorable repeatability, and can implement industrialized large-scale production. By using the method, the content of the genotoxic impurity N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine in the imatinib can be lowered to 2ppm or below according to the pharmacopoeia requirement, and the product purity is up to 99.8% or above.
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Paragraph 0081; 0082; 0083

(2017/10/28)

Synthetic method for imatinib
The invention discloses a synthetic method for imatinib. The synthetic method comprises the following step: adding 4-chloromethyl-N-[4-methyl-3-(4-pyridinyl-3-pyrimidyl-2-amino)phenyl]benzamide into N,N-dimethyl formamide; then adding potassium carbonate with a granularity d (0.5) of no more than 30 [mu]m and N-methylpiperazine; carrying out a heating reaction; and then carrying out after-treatment so as to obtain imatinib. According to the invention, the problems of long reaction time and a great number of impurities in large-scale production are overcome by controlling the granularity of potassium carbonate; the synthetic method is simple to operate; produced imatinib is easy to refine and has high yield and high purity; and the synthetic method is suitable for industrial production.
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Paragraph 0026; 0027; 0028; 0029; 0030; 0031; 0032-0034

(2017/07/20)

Method of refining IMATINIB
The invention relates to a method of refining imatinib. The method comprises the following steps: adding alkaline aqueous liquor into hydrophobic solvent suspension liquid containing imatinib in the form of salt until pH value of the suspension liquid is greater than 14; evaporating out the hydrophobic solvent in an organic phase after phase separation; and adding ethyl acetate into residue, and filtering to obtain high-purity imatinib.
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Paragraph 0086; 0087

(2017/01/19)

Process for the preparation of IMATINIB
A preparing method of imatinib is provided. The method includes: subjecting N-(3-amino-4-methylphenyl)-4-((4-methyl-1-piperazinyl)methyl) benzamide shown as a formula II and a compound shown as a formula V to a coupling reaction shown as follows under existence of an organic alkali to obtain the imatinib. R is selected from a C1-C8 straight-chain or branched-chain alkane, or benzyl, preferably, the R is methyl or ethyl. The method has characteristics of complete reaction, high yield, ideal purity of the imatinib, short technical process, capability of being not related to dangerous or highly toxic harmful compounds, few influences to the environment, and suitability for large-scale production.
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Paragraph 0108; 0109

(2016/12/12)

Methanesulfonic acid iraq Ma Ti nepalese crystalline α and its preparation of pharmaceutical compositions
The invention belongs to the technical field of medicine, relates to preparation of an imatinib mesylate alpha crystal and a pharmaceutical composition thereof, and provides a preparation method of the imatinib mesylate alpha crystal. The method provided by the invention is short in reaction step, simple to operate, small in toxicity of a used solvent, small in environmental pollution, high in total yield, and low in cost. The prepared product is high in purity and applicable to large-scale industrial operation. The crystalline of the prepared imatinib mesylate alpha crystal is over 60%. The pharmaceutical composition containing the imatinib mesylate alpha crystal provided by the invention has the advantages that the defects of poor liquidity, unstable thermodynamics and strong hygroscopicity of the imatinib mesylate alpha crystal are overcome, and the prepared composition is even in content and strong in stability after long-term placement.
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Paragraph 0077-0082

(2017/01/12)

Process for the preparation of IMATINIB
The invention relates to a preparation method of imatinib. The method comprises the following step: performing a reaction on N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine and 4-(4-methyl piperazine methyl) benzoyl chloride dihydrochloride by taking methylene dichloride as a reaction solvent and triethylamine as an alkali.
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Paragraph 0080; 0081

(2016/10/09)

An optimized approach in the synthesis of imatinib intermediates and analogues
We revisited the classical synthetic procedure for imatinib synthesis providing an improved and optimized approach in the preparation of a series of new imatinib analogues. The proposed methodology effectively overcomes certain problematic steps, saves time and labor, provides a very high yield and purity and has the potential to be used for the synthesis of many analogues. The formation of the desired guanidine salt 4, one of the key steps to the imatinib synthesis, was proceeded almost quantitatively by the reaction of the hydrochloride of the suitable aniline 3 with excess of molten cyanamide, without any solvent. Pure arylamine intermediates 6a-d were obtained quantitatively in a short reaction time after reduction of the nitro group of the intermediate pyrimidines 5a-d with hydrogen over the Adam's catalyst. In addition, the application of this optimized approach can be extended in the synthesis of nilotinib and its analogues intermediates.
Kinigopoulou,Filippidou,Gogou,Giannousi,Fouka,Ntemou,Alivertis,Georgis,Brentas,Polychronidou,Voulgari,Theodorou,Skobridis
p. 61458 - 61467
(2016/07/12)

A method for synthesizing of IMATINIB
The invention discloses a synthetic method of imatinib, which relates to the technical field of production processes of western medicines. The method is implemented by taking copper salt and alkali as catalysts and taking N,N'-diisopropylethylenediamine as a ligand through the step of under the protection of nitrogen, in an ether solvent, carrying out hybrid reaction on 4-(3-pyridyl)-2-aminopyrimidine, 4-chloromethyl benzoyl (3-bromo-4-methylphenyl) amine and N-methyl piperazine, so that imatinib is obtained. The invention is a method for synthesizing imatinib in one step by using multiple components, which is short in route and high in efficiency.
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Paragraph 0020-0024

(2017/03/21)

Imatinib preparation method
The invention relates to the technical field of medicine, and in particular, relates to a synthetic process of an anti-tumor medicine. The invention aims to provide an imatinib preparation method which has the advantages of simple operation, easily obtained raw materials, short reaction steps, high yield and environmental friendliness. In the imatinib preparation method, formation of a pyrimidine ring abandons a cyanamide method having relatively great toxicity and a phosphorus oxychloride method having strong corrosion, and by a Suzuki reaction between 2,4-dichloropyrimidine and 3-boric acid pyridine, a key intermediate 2-chloro-4-(3-pyridyl)pyrimidine is rapidly obtained through a one-step method; with use of a characteristic that a 2-site of 2-chloro-4-(3-pyridyl)pyrimidine is easily attacked by a nucleophilic reagent, imatinib is prepared with relatively high conversion rate through a nucleophilic substitution reaction; a metal catalysis method and other methods which are not easy to industrialize and are used in many literatures are discarded. The synthetic process has the advantages of easily obtained raw materials, short reaction steps, high yield and environmental friendliness.
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Paragraph 0040-0043; 0047-0050; 0054-0056

(2017/02/17)

Preparation method of non-acicular alpha crystal form imatinib mesylate
The invention discloses a preparation method of non-acicular alpha crystal form imatinib mesylate. The method comprises the following steps: (1) performing reduction reaction by taking N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-aminopyrimidine as a raw material, methanol as a solvent, KBH4 as a reducing agent and ZrCl4 as a catalyst to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine; (2) after activating 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride hemihydrates by using CBMIT, performing acylation reaction with equimolar N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine by taking DMF as a solvent to obtain imatinib alkali; and (3) suspending the imatinib alkali in isopropanol, adding an acetone solution of methylsulfonic acid, heating for reflux reaction, cooling for crystallization, filtering, and drying to obtain a non-acicular imatinib mesylate alpha crystal form. The preparation method disclosed by the invention has the advantages of being simple in operation, small in environmental harm, safe, reliable, relatively short in reaction time, good in product quality, high in yield and the like, and is suitable for industrial production.
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Paragraph 0042; 0045; 0046

(2016/12/01)

Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs
A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects.
Nicolaou, Kyriacos C.,Vourloumis, Dionisios,Totokotsopoulos, Sotirios,Papakyriakou, Athanasios,Karsunky, Holger,Fernando, Hanan,Gavrilyuk, Julia,Webb, Damien,Stepan, Antonia F.
p. 31 - 37
(2016/01/15)

Use of a "catalytic" Cosolvent, N,N-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib with no Solvent Switch
A general, efficient method for C-N cross-coupling has been developed using N,N-dimethyloctanamide as a catalytic cosolvent for biphasic continuous-flow applications. The described method was used to generate a variety of biarylamines and was integrated into a two-step sequence which converted phenols into biarylamines via either triflates or tosylates. Additionally, the method was applied to a three-step synthesis of imatinib, the API of Gleevec, in good yield without the need of solvent switches. Going with the flow: A general flow method developed for C-N cross-coupling using N,N-dimethyloctanamide as a catalytic cosolvent was integrated into a two-step sequence which converted phenols into biarylamines via either triflates or tosylates. It was applied to a three-step synthesis of imatinib, the API of Gleevec, in good yield without the need of solvent switches.
Yang, Jeffrey C.,Niu, Dawen,Karsten, Bram P.,Lima, Fabio,Buchwald, Stephen L.
p. 2531 - 2535
(2016/02/18)

A Practical Preparation of Imatinib Base
A practical preparation of imatinib base was reported in this article. Compared with reported works, the features of this work were the concise procedures, the industrially available starting materials, the avoidance of expensive or highly toxic transition-metal catalysts or reagents, and the genotoxic impurities 6-methyl-N 1-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine and 4-(chloromethyl)-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide. The method was scalable to at least 100 mmol, and the products were separated by simple recrystallizations.
Zhang, Xu,Sun, Jingjing,Chen, Tian,Yang, Chenggen,Yu, Lei
p. 2233 - 2236
(2016/10/24)

Design and Performance Validation of a Conductively Heated Sealed-Vessel Reactor for Organic Synthesis
A newly designed robust and safe laboratory scale reactor for syntheses under sealed-vessel conditions at 250 °C maximum temperature and 20 bar maximum pressure is presented. The reactor employs conductive heating of a sealed glass vessel via a stainless steel heating jacket and implements both online temperature and pressure monitoring in addition to magnetic stirring. Reactions are performed in 10 mL borosilicate vials that are sealed with a silicone cap and Teflon septum and allow syntheses to be performed on a 2-6 mL scale. This conductively heated reactor is compared to a standard single-mode sealed-vessel microwave instrument with respect to heating and cooling performance, stirring efficiency, and temperature and pressure control. Importantly, comparison of the reaction outcome for a number of different synthetic transformations performed side by side in the new device and a standard microwave reactor suggest that results obtained using microwave conditions can be readily mimicked in the operationally much simpler and smaller conventionally heated device.
Obermayer, David,Znidar, Desiree,Glotz, Gabriel,Stadler, Alexander,Dallinger, Doris,Oliver Kappe
p. 11788 - 11801
(2016/12/09)

Synthetic method of imatinib
A Synthetic method of imatinib is characterized in that with imatinib acid as a raw material, a chlorination reaction is carried out with thionyl chloride with dichloromethane or chloroform as a reaction solvent at normal temperature under normal pressure, wherein the reaction product is directly subjected to an amidation reaction with imatinib amine to synthesize the imatinib through a one-pot method. In the method, the thionyl chloride is employed as a chlorination reagent to perform the chlorination to the imatinib acid in the dichloromethane and the like solvents, wherein the product of the chlorination reaction is directly subjected to the amidation with addition of the imatinib amine. The method simplifies reaction steps and avoids the defect on product yield and quality since imatinib acyl chloride is liable to decompose. The method is simple in steps and operations, is mild in reaction conditions, is high in yield (>= 87%) and product purity (>= 99%), and is suitable for industrial production.
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Paragraph 0023

(2016/12/16)

Synthesizing method of imatinib
The invention relates to the field of organic compound synthesis, in particular to a synthesizing method of imatinib.The materials of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride, N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine, dicyclohexylcarbodiimide and 4-dimethylaminopyridine are added.According to the method, 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride and N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine are added to an organic solution of dicyclohexylcarbodiimide, the catalyst 4-dimethylaminopyridine is added, imatinib is synthesized in one step, the production efficiency is improved, and meanwhile the production cost is reduced.Meanwhile, the dehydrating agent dicyclohexylcarbodiimide is used, the reaction between 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride and N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine is thorough, dicyclohexylurea (DCU) is generated from dicyclohexylcarbodiimide (DCC) after the reaction is completed, recycling can be achieved, and the degree of contamination is reduced.
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Paragraph 0018; 0024; 0025

(2016/10/27)

PROCESS FOR PREPARING IMATINIB AND SALTS THEREOF, FREE OF GENOTOXIC IMPURITY F
The invention relates to an improved process for the preparation of Imatinib and salts thereof, in particular Imatinib Mesylate, having a content of a particular genotoxic impurity, named impurity F, within the pharmacopeia limits.
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Paragraph 0088-0089

(2015/11/16)

A method of manufacturing a crystal type α pridinol Imanitib
The present invention provides a method for preparing the alpha-crystalline form of imatinib mesylate. The method of the present invention may involve using a mixed solvent as a reaction solvent to significantly reduce the content of isopropyl alcohol remaining in the alpha-crystalline form of imatinib mesylate ultimately obtained.
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Paragraph 0051; 0052

(2018/10/19)

Design, Synthesis, and Characterization of a Photoactivatable Caged Prodrug of Imatinib
Imatinib is the first protein kinase inhibitor approved for clinical use and is a seminal drug for the concept of targeted therapy. Herein we report on the design, synthesis, photokinetic properties, and in vitro enzymatic evaluation of a photoactivatable caged prodrug of imatinib. This approach allows spatial and temporal control over the activation of imatinib triggered by ultraviolet light. The successful application of the photoactivation concept to this significant kinase inhibitor provides further evidence for the caging technique as a feasible approach in the kinase field. The presented photoactivatable imatinib prodrug will be highly useful as a pharmacological tool to study the impact of imatinib toward biological systems in greater detail. Don′t fence me in! A caged prodrug of imatinib, the first approved kinase inhibitor, was designed, synthesized, and characterized for photokinetic properties. By using a PDGF-Rβ assay, we demonstrated that upon UV irradiation at λ=365nm the biological activity of imatinib is restored.
Zindler, Melanie,Pinchuk, Boris,Renn, Christian,Horbert, Rebecca,D?bber, Alexander,Peifer, Christian
p. 1335 - 1338
(2015/08/03)

PROCESS FOR PREPARING IMATINIB AND IMATINIB MESYLATE NON-NEEDLE SHAPED α2 FORM
The present invention relates to an efficient process and industrially feasible for the preparation of imatinib and imatinib mesylate non-needle shaped α2 form with high purity, without requiring purification by recrystallization or column chromatography. The process of the present invention is easy, fast and economical, wherein the imatinib mesylate is obtained with high yield and purity.
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Page/Page column 8; 22; 23

(2016/01/01)

Imatinib analogs as potential agents for PET imaging of Bcr-Abl and c-KIT expression at a kinase level
We synthesized two series of imatinib mesylate (STI-571) analogs to develop a Bcr-Abl and c-KIT receptor-specific labeling agent for positron emission tomography (PET) imaging to measure Bcr-Abl and c-KIT expression levels in a mouse model. The methods of molecular modeling, synthesis of STI-571 and its analogs, in vitro kinase assays, and radiolabeling are described. Molecular modeling revealed that these analogs bind the same Bcr-Abl and c-KIT binding sites as those bound by STI-571. The analogs potently inhibit the tyrosine kinase activity of Bcr-Abl and c-KIT, similarly to STI-571. [ 18F]-labeled STI-571 was prepared with high specific activity (75 GBq/μmol) by nucleophilic displacement and an average radiochemical yield of 12%. [131I]-labeled STI-571 was prepared with high purity (>95%) and an average radiochemical yield of 23%. The uptake rates of [ 18F]-STI-571 in K562 cells expressing Abl and in U87WT cells overexpressing c-KIT were significantly higher than those in the U87 cell and could be inhibited by STI-71 (confirming the specificity of uptake). PET scans of K562 and U87WT tumor-bearing mice with [18F]-STI-571 as a contrast agent showed visible tumor uptake and tumor-to-non-target contrast.
Peng, Zhenghong,Maxwell, David S.,Sun, Duoli,Bhanu Prasad, Basvoju A.,Pal, Ashutosh,Wang, Shimei,Balatoni, Julius,Ghosh, Pradip,Lim, Seok T.,Volgin, Andrei,Shavrin, Aleksander,Alauddin, Mian M.,Gelovani, Juri G.,Bornmann, William G.
p. 623 - 632
(2014/01/17)

INTERMEDIATES FOR A NOVEL PROCESS OF PREPARING IMATINIB AND RELATED TYROSINE KINASE INHIBITORS
4-Oxo-2-phenylaminopyrimidine derivatives as intermediates for synth of tyrosine kinase inhibitors, in particular imatinib and nilotinib.
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(2013/08/28)

PROCESSES FOR THE PREPARATION OF IMATINIB BASE AND INTERMEDIATES THEREOF
The invention relates to an improved process for the preparation of highly pure imatinib base (99.99% HPLC purity) of formula (I) and the pharmaceutically acceptable acid addition salts thereof. This invention also relates to processes for the preparation of the intermediates in the synthesis of imatinib base.
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Page/Page column 22; 23

(2013/03/26)

New Method for Synthesizing Imatinib
In the present invention, a synthesis method of Imatinib is disclosed, which comprises the following steps: the Imatinib, namely 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-[4-(3-pyridinyl)-pyrimidin-2-ylamino]-benzamide shown in formula (III), is formed by reacting 4-methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)-1,3-benzenediamine shown in formula (I) with 4-(4-methyl-piperazin-1-methyl)-benzoic ester shown in formula (II), under the action of a base and in a non-protonic organic solvent, in the above generic chemical structural formula, R represents aliphatic alkyl having 1-10 carbon, phenyl, substituted phenyl, benzyl or substituted benzyl. The present invention provides a new synthesis method of Imatinib, which is formed under mild reaction conditions, and is environmentally friendly with a high-yield.
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Paragraph 0033

(2013/03/26)

Rapid discovery of a novel series of Abl kinase inhibitors by application of an integrated microfluidic synthesis and screening platform
Drug discovery faces economic and scientific imperatives to deliver lead molecules rapidly and efficiently. Using traditional paradigms the molecular design, synthesis, and screening loops enforce a significant time delay leading to inefficient use of data in the iterative molecular design process. Here, we report the application of a flow technology platform integrating the key elements of structure-activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors. The platform utilizes flow chemistry for rapid in-line synthesis, automated purification, and analysis coupled with bioassay. The combination of activity prediction using Random-Forest regression with chemical space sampling algorithms allows the construction of an activity model that refines itself after every iteration of synthesis and biological result. Within just 21 compounds, the automated process identified a novel template and hinge binding motif with pIC50 > 8 against Abl kinase - both wild type and clinically relevant mutants. Integrated microfluidic synthesis and screening coupled with machine learning design have the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases.
Desai, Bimbisar,Dixon, Karen,Farrant, Elizabeth,Feng, Qixing,Gibson, Karl R.,Van Hoorn, Willem P.,Mills, James,Morgan, Trevor,Parry, David M.,Ramjee, Manoj K.,Selway, Christopher N.,Tarver, Gary J.,Whitlock, Gavin,Wright, Adrian G.
supporting information
p. 3033 - 3047
(2013/05/22)

An expeditious synthesis of imatinib and analogues utilising flow chemistry methods
A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.
Hopkin, Mark D.,Baxendale, Ian R.,Ley, Steven V.
p. 1822 - 1839
(2013/04/23)

METHOD FOR PRODUCING IMATINIB BASE
The present invention relates to a novel method for preparing an imatinib base, and more particularly to a method for preparing an imatinib base, which comprises reacting 4-(4-methyl-piperazinomethyl)-benzoic acid with a 2,2′-dibenzothiazolyl disulfide derivative in the presence of a phosphine derivative to prepare a novel thioester compound and preparing an imatinib base using the thioester compound as a reaction intermediate. In addition, the invention provides a novel thioester compound, which is used in the preparation of imatinib base, and a preparation method thereof. Ultimately, the invention provides a method of preparing the imatinib base in an economic manner and in high yield and purity and is expected to be used in the commercial production of large amounts of the imatinib base.
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Page/Page column 10

(2013/02/28)

Process for the Preparation of Imatinib Base
Provided is an environmentally-friendly process for preparing imatinib base in high yield, without the use of an organic solvent.
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Page/Page column 5-6

(2012/03/10)

A facile total synthesis for large-scale production of imatinib base
An efficient, economic process has been developed for the production of imatinib with 99.99% purity and 50% overall yield from four steps. Formation and control of all possible impurities is described. The synthesis comprises the condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine with 4-(4-methylpiperazinomethyl)benzoyl chloride in isopropyl alcohol solvent in the presence of potassium carbonate to yield imatinib base.
Kompella, Amala,Adibhatla, Bhujanga Rao Kalisatya,Muddasani, Pulla Reddy,Rachakonda, Sreenivas,Gampa, Venugopala Krishna,Dubey, Pramod Kumar
p. 1794 - 1804
(2013/01/15)

IMPROVED PROCESS FOR PREPARATION OF IMATINIB AND ITS MESYLATE SALT
Disclosed is a process for the preparation of imatinib of formula (I), or its mesylate salt with controlled level of genotoxic impurity of formula (II), a key intermediate for imatinib.
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Page/Page column 14-15

(2012/10/18)

PROCESS FOR THE PREPARATION OF IMATINIB MESYLATE
The present application relates to process for the preparation of imatinib mesylate. This application also relates to the processes for preparation of alpha crystalline form of imatinib mesylate.
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Page/Page column 26-27

(2012/02/13)

Novel method for preparing imatinib base
The present invention relates to a novel method for preparing an imatinib base, and more particularly to a method for preparing an imatinib base, which comprises reacting 4-(4-methyl-piperazinomethyl)-benzoic acid with a 2,2'-dibenzothiazolyl disulfide derivative in the presence of a phosphine derivative to prepare a novel thioester compound and preparing an imatinib base using the thioester compound as a reaction intermediate. In addition, the invention provides a novel thioester compound, which is used in the preparation of imatinib base, and a preparation method thereof. Ultimately, the invention provides a method of preparing the imatinib base in an economic manner and in high yield and purity and is expected to be used in the commercial production of large amounts of the imatinib base.
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Page/Page column 11

(2012/12/14)