Synthesis of imatinib: a convergent approach revisited

Abstract  

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.     

伊马替尼衍生物的合成及细胞毒活性研究

以3-乙酰基嘧啶、2-甲基-5-硝基苯胺为起始原料,经加成、缩合、环化、还原得到中间体伊马替胺(6),再与异氰酸酯和芳酰基异硫氰酸酯胺解得到脲类(7a~7e)和芳酰基硫脲类(8a~8g)共12个化合物。目标化合物经过IR、1H NMR、13C NMR、HRMS等结构确证。采用四甲基偶氮唑盐(MTT)法考察目标化合物细胞毒活性,结果显示,目标化合物对所选肿瘤细胞的增殖活性具有一定抑制作用,其中化合物7d、7e、8d对人白血病细胞(K562)和人肝癌细胞(Hep G2)的抑制活性接近伊马替尼。     

A novel approach for the synthesis of aryl amides

A novel and highly efficient approach for the synthesis of aryl amides in high yields by the reaction of carboxylic acids and isocyanides in methanol at ambient temperature is reported.     

A facile direct conversion of aldehydes to esters and amides using acetone cyanohydrin

Aromatic aldehydes with electron-withdrawing groups undergo rapid reactions with a variety of alcohols and secondary amines to afford the corresponding esters and amides, respectively, in high yields, when treated with NaCN or acetone cyanohydrin and base under ambient reaction conditions. In case of α,β-unsaturated aldehydes, simultaneous reduction of the CC bond along with esterification occurred to produce the saturated esters in high yields.     

The (salophen)-bridged Fe/Cr (III) capped complexes with triphenylene core: Synthesis and characterization

This article describes synthesis of the difference carboxylic acid derivatives of triphenylene and its complexation properties with Fe/Cr (III)-salophen. For this purpose, the carboxylic acid derivatives of 2,3,6,7,10,11-hexahydroxytriphenylene were synthesized and then reacted with four new Fe(III) and Cr(III) complexes involving tetradenta Schiff bases bis(salicylidene)-o-phenylenediamine-(salophenH₂). The prepared compounds were characterized by means of elemental analysis carrying out infrared spectroscopy (IR), thermogravimetric analysis (TG), nuclear magnetic resonance (¹H NMR), elemental analysis and magnetic susceptibility measurement. The complexes can also be characterized as low-spin distorted octahedral Fe(III) and Cr (III) bridged by carboxylic acids.     

Nonaqueous capillary electrophoresis of imatinib mesylate and related substances

In the present study, nonaqueous capillary electrophoretic separation of imatinib mesylate (IM) and related substances, N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (PYA), N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((piperazin-1-yl)methyl) benzamide (NDI) and 4-chloromethyl-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (CPB) was developed. The influential factors affecting separation, including type and concentration of the electrolyte, applied voltage, and buffer modifier were investigated. Baseline separation of the studied analytes was obtained using a buffer of 50 mM Tris and 50 mM methanesulfonic acid in methanol at a apparent pH (pH*) of 1.65. To enhance the sensitivity, large-volume sample stacking was employed for online concentration. The strongest analytical signal with a suitable separation was achieved when the injection time was 100 s. The linearity ranges of PYA and NDI were 0.100-2.50 μg mL(-1) , and that of CPB was 0.125-2.50 μg mL(-1) , with good coefficients (r(2) > 0.9948). The relative standard deviations of intra- and interday were satisfactory. Under the optimized conditions, seven batches of the synthesized samples were analyzed and CPB was detected in two batches. Owing to its simplicity, effectiveness, and low price, the developed method is promising for quality control of IM.     

Synthesis of 1,5-bifunctional organolithium reagents by a double directed ortho-metalation: Direct transformation of esters into 1,8-dimethoxy-acridinium salts

The impact of electronic and steric factors on the selectivity of the electrophilic aromatic substitution amounts to several limitations in accessing specific substitution patterns. Nucleophiles generated by directed metalation represent an effective alternative for the preparation of various distinctly substituted arenes and heterocyclic scaffolds to overcome these restraints. Herein, we report the direct synthesis of specifically substituted heterocyclic fluorophores from esters by the addition of 1,5-bifunctional organometallic reagents from a double directed ortho-metalation (dDoM). Bis(3-methoxyphenyl)amines were efficiently dilithiated and employed for the synthesis of 1,8-dimethoxy-acridinium salts with distinct photophysical and electrochemical properties. The individual reduction potentials, the water-solubility and the brightness of these new dyes promise different applications in catalysis, imaging and materials science.     

Synthesis and spectroscopic studies of 3-carbamoylisonicotinic acid derivatives

An unusual example of the selective hydrolysis of a cyano group to the corresponding carboxyl group under mild reaction conditions in the presence of a carboxamide group is reported. The reaction resulted in the formation of a rare combination of vicinal carboxamide and carboxyl groups on a pyridone ring. The structure of the synthesized products was thoroughly studied using one- and two-dimensional NMR experiments and the reaction pathway was monitored fluorometrically.     

Synthesis of the penta-oxazole core of telomestatin in a convergent approach to poly-oxazole macrocycles

A protocol for the construction of poly-oxazoles with consecutive 2,4'-linkages is described, and has afforded an efficient route to a penta-oxazole which demarcates a route to telomestatin and related macrocyclic poly-oxazole systems.     

Application of zirconium-modified silica gel as a stationary phase in the ion-exclusion chromatography of carboxylic acids II. Separation of aliphatic carboxylic acids with pyromellitic acid as eluent and with suppressed conductimetric detection

The application of zirconium-modified silica gels (Zr-Silica) as stationary phases for ion-exclusion chromatography with conductimetric detection (IEC–CD) for C₁–C₈ aliphatic carboxylic acids (formic, acetic, propionic, butyric, valeric, caproic, heptanoic and caprylic acids) was carried out using pyromellitic acid as the eluent. Zr-Silicas were prepared by the reaction of the silanol group on the surface of silica gel with zirconium tetrabutoxide [Zr(OCH₂CH₂CH₂CH₃)₄] in ethanol solution. An ASRS-Ultra anion self-regenerating suppressor in the K⁺ form was used for the enhancement of conductimetric detector response of these aliphatic carboxylic acids. A Zr-Silica adsorbed on 10 mg zirconium g⁻¹ silica gel was the most suitable stationary phase in IEC–CD for the separation of these aliphatic carboxylic acids. Excellently simultaneous separation and highly sensitive detection for these aliphatic carboxylic acids were achieved in 25 min by IEC–CD with the Zr-Silica column (250×4.6 mm I.D.) and a 0.2 mM pyromellitic acid containing 0.15% heptanol as the eluent.     

Structure and magnetism of a new 2-D trinuclear Mn(II) polymer

A new complex, {[Mn₃(oba)₂(IP)₂(CH₃COO)₂]·H₂O}_n (1) (H₂oba?=?4,4′-oxybis(benzoic acid), IP?=?1-H-imidazo[4,5-f][1,10]-phenanthroline), has been synthesized and structurally characterized by single-crystal diffraction analysis. The structural determination revealed that 1 has a 2-D grid motif, which can be further linked into a 3-D porous network via packing interactions. The magnetic properties of 1 are discussed.     

An unexpected coupling reaction between isocyanides and carboxylic acids: a method for the synthesis of highly stable symmetrical and unsymmetrical alkylamidine and arylamidine carbocations

An unexpected coupling reaction between isocyanides and carboxylic acids which led to the synthesis of highly stable symmetrical and unsymmetrical alkylamidine and arylamidine carbocations under mild reaction conditions is described. The structures of these compounds were confirmed by IR, mass, ¹H NMR, ¹³C NMR, and single-crystal X-ray diffraction studies and a plausible mechanism is proposed.     

A one-pot procedure for trifluoroacetylation of arylamines using trifluoroacetic acid as a trifluoroacetylating reagent

A convenient procedure for the preparation of aryl trifluoroacetamides from aryl amines is described that employs 2-4 M equiv of trifluoroacetic acid in refluxing xylene as a trifluoroacetylating agent. Addition of an amount of pyridine that is equimolar to the amount of trifluoroacetic acid present in the reaction mixture facilitates the trifluoroacetylation of rather basic arylamines.     

Synthesis of Arylamines via Aminium Radicals

Arylamines constitute the core structure of many therapeutic agents, agrochemicals, and organic materials. The development of methods for the efficient and selective construction of these structural motifs from simple building blocks is desirable but still challenging. We demonstrate that protonated electron‐poor O‐aryl hydroxylamines give aminium radicals in the presence of Ru(bpy)₃Cl₂. These highly electrophilic species undergo polarized radical addition to aromatic compounds in high yield and selectivity. We successfully applied this method to the late‐stage modification of chiral catalyst templates, therapeutic agents, and natural products.     

Synthesis and structure of potential Lewis acid–Lewis base bifunctional catalysts: 1-N,N-dimethylamino-8-borononaphthalene derivatives

A new series of boronate-amine substituted potential bifunctional catalysts have been prepared by directed lithiation of 1-N,N-dimethylnaphthalene, followed by reaction borate esters. Both diisopropyl and pincacol ester derivatives of the resulting boronates were prepared, together with a novel boroxine which shows novel N–B interactions in the crystal structure. The corresponding dimethyl-[8-(difluoroborolyl)-naphthalen-1-yl]-amine was directly accessed from the boroxine by reaction with potassium hydrogen fluoride.     

A Convenient Synthesis of Disulfides and Sulfenamides

We report the synthesis of disulfides from thiols through the use of morpholine-iodine complex. The method is yet another procedure for the preparation of the title compounds.     

Synthesis of n-butyl ester and n-butylamide of methyl-phenylphosphinic acid: Two case studies

n-Butyl methyl-phenylphosphinate and methyl-phenylphosphinic n-butylamide were synthesized by different methods: the reaction of methyl-phenylphosphinic chloride with ⁿBuOH or ⁿBuNH₂, respectively, the T3P®-promoted derivatization of methyl-phenylphosphinic acid with ⁿBuOH or ⁿBuNH₂, the microwave-assisted direct esterification of the model phosphinic acid, and finally the alkylating esterification with n-butyl bromide under phase-transfer-catalytic and microwave-assisted conditions. The different methods, mostly elaborated by us, were compared from practical and environmentally friendly points of view.     

5H-3-oxa-Octafluoropentanesulfonyl fluoride: a novel and efficient condensing agent for esterification, amidation and anhydridization

The use of 5H-3-oxa-octafluoropentanesulfonyl fluoride (HCF₂CF₂OCF₂CF₂SO₂F) as a novel and efficient condensing reagent for esterification of carboxylic acids with alcohols and amidation of carboxylic acids with amines in the presence of 1,3-diazabicyclo[5.4.0]-undec-7-ene (DBU) is reported. HCF₂CF₂OCF₂CF₂SO₂F cannot serve as a condensing agent for anhydridization of carboxylic acids, however, HCF₂CF₂OCF₂CF₂SO₂F/(CH₃)₃SiCN system can mediate anhydridization of some aromatic carboxylic acids.     

Synthesis and characterisation of poly(ester-amide)s from aromatic bisoxazoline precursors

A series of novel aliphatic aromatic poly(ester-amide)s (PEA) have been synthesized by condensation reaction of aromatic bisoxazolines with aliphatic dicarboxylic compounds. These polymers have a number average molecular weight of 20,000-25,000. Depending of the aromatic structure of the bisoxazoline precursor, they are either amorphous or semi-crystalline. A good solubility in aprotic solvents was observed for all PEAs.