New synthetic method for 2,3,4-tris(hydroxymethyl)- 6-methylpyridin-5-ol

Shtyrlin, Nikita V.; Strel’nik, A. D.; Sysoeva, L. P.; Лодочникова, О. А.; Klimovitskii, E. N.; Shtyrlin, Yu. G.

doi:10.1134/s1070428009080314

Cited by 22 publications

(6 citation statements)

References 7 publications

(10 reference statements)

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“…1. Chloride 2 was synthesized from initial pyridoxine hydrochloride 1 using our previously reported methods 13 – 15 . Interaction of 2 with Na 2 S or Na 2 S 2 in the presence of catalytic amounts of tert-butyl ammonium bromide (TBAB) in a heterophase H 2 O-CHCl 3 medium led to dimers 3 and 4 , respectively.…”

Section: Resultsmentioning

confidence: 99%

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus

Dzyurkevich

Babkov

Shtyrlin

et al. 2017

Sci Rep

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Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 μM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%). Both leading compounds demonstrated low cytotoxicity and excellent safety profile in acute toxicity experiment in rats after oral administration with LD50 exceeding 2000 mg/kg of body weight. Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellitus, as well as a promising starting point for the design of structural analogs with improved activity.

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Section: Resultsmentioning

confidence: 99%

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus

Dzyurkevich

Babkov

Shtyrlin

et al. 2017

Sci Rep

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“…The reaction of compound 4 with pivaldehyde in the presence of toluenesulfonic acid at reflux temperature using a Dean‐Stark trap led to the formation of a six‐membered acetal 5 . Chlorine derivative 6 was obtained via chlorination of the hydroxymethyl group of compound 5 using thionyl chloride as the chlorinating agent.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of a new quaternary phosphonium salt: NMR study of the conformational structure and dynamics

et al. 2015

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A novel phosphonium salt based on pyridoxine was synthesized. Conformational analysis of the compound in solution was performed using dynamic NMR experiments and calculations. The obtained results revealed some differences in the conformational transitions and the energy parameters of the conformational exchange of the studied compound in comparison to previously reported data for other phosphorus-containing pyridoxine derivatives. It was shown that increasing the substituent at the C-11 carbon leads to greater differences in the populations of stable states and the corresponding equilibrium energies. Copyright © 2015 John Wiley & Sons, Ltd.

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“…We previously developed a new procedure for the synthesis of 6-methyl-2,3,4-tris(hydroxymethyl)pyridin-5-ol and performed experimental and theoretical studies on cyclic acetonides based thereon [2,3]. While continuing systematic studies on 6-substituted pyridoxine derivatives, in the present work we developed synthetic approaches to previously unknown pyridoxine derivatives containing hydroxymethyl groups in positions 2 and 6, which provided additional possibilities for subsequent functionalization.…”

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confidence: 96%

Experimental and theoretical study on 6-substituted pyridoxine derivatives. Synthesis of cyclic 2,4,5,6-tetrakis-(hydroxymethyl)pyridin-3-ol acetonides

et al. 2011

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Synthetic approaches to three cyclic 2,4,5,6-tetrakis(hydroxymethyl)pyridin-3-ol acetonides were developed. Among seven possible mono-and diketals, six-membered cyclic ketal incorporating the hydroxymethyl group in the 4-position turned out to be the most thermodynamically favorable. The experimental data were consistent with the results of quantum-chemical calculations of the Gibbs energies of formation of different acetonides. The structure of the isolated compounds was studied by X-ray diffraction. † Deceased.Functionalization of natural biologically active compounds is one of the most important ways of the design of new medical agents. Such a compound is vitamin B 6 which is incorporated into more than hundred enzymes involved in biosynthesis, metabolism, and regulatory functions in living organism [1].We previously developed a new procedure for the synthesis of 6-methyl-2,3,4-tris(hydroxymethyl)pyridin-5-ol and performed experimental and theoretical studies on cyclic acetonides based thereon [2,3]. While continuing systematic studies on 6-substituted pyridoxine derivatives, in the present work we developed synthetic approaches to previously unknown pyridoxine derivatives containing hydroxymethyl groups in positions 2 and 6, which provided additional possibilities for subsequent functionalization. The key step in the developed approach was rearrangement of the corresponding N-oxide. This rearrangement was used previously to modify methyl group in position 2 of the pyridine ring to obtain the corresponding hydroxymethyl derivative [4,5].In the first step, 6-hydroxymethyl-3,3,8-trimethyl-1,5-dihydro[1,3]dioxepino[5,6-c]pyridin-9-ol (I) was subjected to acylation with acetic anhydride. 9-Acetoxy-6-acetoxymethyl-3,3,8-trimethyl-1,5-dihydro[1,3]-dioxepino[5,6-c]pyridine (II) thus obtained was oxidized with m-chloroperoxybenzoic acid, and N-oxide III underwent rearrangement in acetic anhydride. The rearrangement selectively involved the methyl group in position 2 of the pyridine ring. All these three steps occurred smoothly and were characterized by high yields (Scheme 1). An attempt to synthesize 2,4,5,6-tetrakis(hydroxymethyl)pyridin-3-ol (VII) by simultaneous removal of all protecting groups in 9-acetoxy-6,8-bis(acetoxymethyl)-3,3-dimethyl-1,5-dihydro[1,3]-dioxepino[5,6-c]pyridine (IV) in acidic medium was unsuccessful (the reaction was accompanied by strong tarring). We succeeded in isolating 6,8-bis(hydroxymethyl)-3,3-dimethyl-1,5-dihydro[1,3]dioxepino-[5,6-c]pyridin-9-ol (V) only with the use of sodium ethoxide, whereas other reagents (such as sodium hydroxide or potassium carbonate in methanol) gave rise to inseparable mixtures of products.Cyclic acetal V turned out to be unstable; on storage at 20°C over a period of two weeks even with protection from atmospheric oxygen and moisture, it underwent appreciable tarring with formation of a number of compounds. By contrast, six-membered

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New synthetic method for 2,3,4-tris(hydroxymethyl)- 6-methylpyridin-5-ol

Cited by 22 publications

References 7 publications

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus

Synthesis of a new quaternary phosphonium salt: NMR study of the conformational structure and dynamics

Experimental and theoretical study on 6-substituted pyridoxine derivatives. Synthesis of cyclic 2,4,5,6-tetrakis-(hydroxymethyl)pyridin-3-ol acetonides

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