- Evaluation of 2-methyl-3-hydroxy-4-pyridinecarboxylic acid as a possible chelating agent for iron and aluminium
-
In view of a possible application to Fe and Al chelation therapy, 2-methyl-3-hydroxy-4-pyridinecarboxylic acid (DT2) was synthesised, and its complex formation, electrochemical and cytotoxic properties were studied. The complexing properties of DT2 towards Fe(iii) and Al(iii) were investigated in aqueous 0.6 m (Na)Cl at 25 °C by means of potentiometric titrations, UV-vis spectrophotometry, and 1H NMR spectroscopy. DT2 is a triprotic acid (H3L+) having pKa1 = 0.47, pKa2 = 5.64 and pKa3 = 11.18. The metal-ligand complexes observed in solution and their corresponding stability constants (logβ values) are the following: FeLH (19.38), FeL (16.01), FeLH-1 (12.28), FeL 2H2 (37.29), FeL3H3 (53.41), FeL3H2 (47.99), FeL3H (41.21) and FeL 3 (34.1); AlLH (17.43), AlL2H2 (33.74), AlL2H (27.6), AlL3H3 (48.72), AlL 3H2 (42.67), AlL3H (35.8) and AlL3 (27.92). The complex formation between DT2 and Fe(ii) was studied by UV-vis: the weak complex FeLH (logβ = 15.8) was detected. DT2 shows a lower complexation efficiency with Fe(iii) and Al(iii) than that of other available chelators, but higher than that of its non-methylated analogue 3-hydroxy-4-pyridinecarboxylic acid (DT0). The electrochemical behaviour of DT2 was investigated by means of cyclic voltammetry, indicating that the oxidation of the ligand proceeds through a two electron process with a CECE mechanism. Voltammetric curves suggest that the oxidation or the reduction of DT2 in vivo is unlikely. According to the thermodynamic data, also the Fe(iii)-DT2 complexes do not undergo redox cycling at physiological pH. Amperometric titrations of solutions containing Fe(iii) and DT2 at pH = 5 indicated the same Fe(iii): ligand stoichiometric ratio as calculated from potentiometric data. The toxicity of DT2 and of other simple hydroxypyridinecarboxylic acids was investigated in vitro and no cytotoxic activity was observed (IC50 > 0.1 mM) on cancer cell lines and also on primary human cells, following a three day exposure. The Royal Society of Chemistry.
- Dean, Annalisa,Ferlin, Maria Grazia,Brun, Paola,Castagliuolo, Ignazio,Badocco, Denis,Pastore, Paolo,Venzo, Alfonso,Bombi, G. Giorgio,Di Marco, Valerio B.
-
-
Read Online
- Environment-friendly preparation method of substituted oxazole compound
-
The invention provides an environment-friendly preparation method of a substituted oxazole compound, which takes N-substituted formyl alpha-substituted glycine ester as an initial raw material; the substituted oxazole compound is obtained through a cyclization reaction under the action of a dehydrating agent such as trisubstituted phosphine dihalide, a combination of trisubstituted phosphine dihalide and an acyl halide reagent or a combination of trisubstituted phosphine oxide and an acyl halide reagent and organic amine. The obtained substituted oxazole compound can be further saponified anddecarboxylated to obtain a medical intermediate 4-substituent-5-substituent oxazole. The method can be carried out in a continuous flow manner, so that the production efficiency is improved, and the operation is reduced; a byproduct trisubstituted phosphine oxide is generated in the reaction process and can be recycled, so that the cost is reduced; phosphorus oxychloride and phosphorus pentoxide which are high in price and large in preparation process wastewater amount are not used as dehydrating agents, a high-temperature cyclization reaction is not needed, the process is simple, operation iseasy and convenient, no phosphorus-containing wastewater is discharged, and the method is environmentally friendly and low in cost. The method is high in atom economy, high in target product yield and purity and suitable for industrial application.
- -
-
-
- Preparation method of 4-methyl-5-ethoxy oxazole
-
The invention discloses a preparation method of 4-methyl-5-ethoxy oxazole, which comprises the following steps of by using N-formyl alanine ethyl ester as a raw material, directly cyclizing in the presence of boron trifluoride diethyl etherate and metal oxide to obtain 4-methyl-5-ethoxy oxazole, which has a reaction general formula (1). The preparation method of the novel 4-methyl-5-ethoxy oxazole is short in route, simple to operate, high in conversion rate and good in atom economy, the used materials such as boron trifluoride diethyl ether can be recycled and reused, a large amount of wastewater cannot be generated, and the preparation method is very suitable for industrial production.
- -
-
Paragraph 0005; 0016-0039
(2021/04/26)
-
- Preparation method of 4-alkyl-5-alkoxy oxazole compound
-
The invention discloses a preparation method of a 4-alkyl-5-alkoxy oxazole compound. The preparation method comprises the following steps: under the action of a catalyst, carrying out transesterification on 4-alkyl-5-alkoxy oxazole-2-carboxylic ester and acid in a solvent to obtain an oxazole acid intermediate, and carrying out decarboxylation reaction on the oxazole acid intermediate to obtain the 4-alkyl-5-alkoxy oxazole compound. The preparation method has the advantages of no wastewater generation in the reaction process, cheap and accessible catalyst and high reaction yield, and is convenient for industrial production.
- -
-
Paragraph 0040-0041
(2020/02/14)
-
- Method for preparing oxazole compound
-
The invention relates to a method for preparing an oxazole compound. The method comprises the steps: adding an assistant represented by a formula (I) or (II) or (III) into an organic solvent and organic alkali (especially triethylamine), dropwise adding an organic solution of phosgene or diphosgene or triphosgene to carry out cyclization reaction with a compound (IV), and thus obtaining the product (V) at high yield and greatly inhibiting the generation of byproducts. The reaction conditions are mild, and compared with a method without addition of additives, the method provided by the invention can improve the yield of the product (V) to 95% or above and reduce the yield of byproducts by 10% or above.
- -
-
Paragraph 0060-0065; 0084-0089
(2020/06/05)
-
- Synthetic method for continuous saponification and decarboxylation of 4-methyl-5-ethoxyoxazole
-
The invention belongs to the field of compound synthesis, and discloses a synthetic method for continuous saponification and decarboxylation of 4-methyl -5ethoxy oxazole, which comprises the followingsteps: premixing an organic solution containing 4-methyl- 5-ethoxy oxazole acid ethyl ester with alkali, and continuously pumping the mixture into a tubular reactor I for saponification reaction; premixing the obtained saponification liquid with acid and alcohol, continuously pumping the mixture into a tubular reactor II for decarboxylation reaction, discharging the obtained decarboxylation liquid from an outlet of the tubular reactor II, and performing post-treatment to obtain the 4-methyl- 5-ethoxy oxazole. The tubular reactor is adopted for continuous saponification and decarboxylation reaction, so that the reaction time can be remarkably shortened, the reaction yield is increased, the water vapor stripping step is reduced, the saponified reaction liquid does not need to be subjected to operations such as layered extraction, the reaction process flow is shortened, and the energy consumption is reduced.
- -
-
Paragraph 0045; 0047-0061
(2020/11/23)
-
- Synthesis method of 4-methyl-5-ethyoxy oxazole
-
The invention discloses a synthesis method of 4-methyl-5-ethyoxy oxazole. The synthesis method comprises the following steps: sequentially adding methylbenzene, N-ethoxyoxoacetyl alanine ethyl ester,triethylamine and phosphorus oxychloride, and heating for a cyclization reaction; adding water and liquid caustic soda into the product of the cyclization reaction; when the pH value shows alkalinity,performing a saponification reaction; after layering of the saponification reaction product, collecting the lower-layer reactant; adding an aqueous solution of hydrochloric acid into the lower-layerreactant till acidity, and heating for reacting, wherein the lower-layer reactant sequentially experiences acidification and decarboxylation to obtain a product solution generating 4-methyl-5-ethoxy oxazole; neutralizing the product solution with alkali till neutrality, and performing separation and purification to obtain 4-methyl-5-ethoxy oxazole. According to the synthesis method disclosed by the invention, the synthesis technology of 4-methyl-5-ethoxy oxazole is optimized, and the wastewater generated in the technological process is reduced.
- -
-
-
- Preparation method for 4-methyl-5-alkoxyoxazole
-
The invention discloses a preparation method for 4-methyl-5-alkoxyoxazole, and belongs to the field of chemical synthesis. The method includes the following steps: a cyclization reaction is performedon N-formylalanine esters to obtain the 4-methyl-5-alkoxyoxazole, and the cyclization reaction is performed in presence of a solid acid catalyst. A purposed of the invention is to provide a preparation method for the 4-methyl-5-alkoxyoxazole, which has the characteristics of less reaction step, high yield, less discharge capacity of waste liquid, easy treatment of pollution and low production cost. The method of the invention can be applied to laboratory preparation or industrial production and is used for preparation of a vitamin B6 synthetic intermediate.
- -
-
Paragraph 0125-0126; 0129-0132
(2019/11/21)
-
- Method for preparing 4-methyl-5-ethoxazole
-
The invention relates to a method for preparing a key intermediate 4-methyl-5-ethoxazole of vitamin B6 and belongs to the technical field of crude drug preparation. The method for preparing 4-methyl-5-ethoxazole comprises the steps that firstly, 4-methyl-5-ethyoxyl-1,3-oxazole-2-nonanoic acid-ethyl ester, methylbenzene, drinking water and sodium hydroxide are sequentially put into a hydrolysis reaction still according to a certain proportion, and stirring, heat preservation and reacting are carried out; liquid separation is carried out, and the pH value of the water phase is adjusted to rangefrom 1.0 to 2.5; an organic solvent is added to the system obtained in the second step, reacting is carried out by controlling the temperature ranging from 30 DEG C to 50 DEG C until no carbon dioxideis generated; after decarboxylation is finished, the pH value is adjusted to be larger than or equal to 9.0, liquid separation is carried out, the organic phase is subjected to vacuum distillation, and 4-methyl-5-ethoxazole is obtained. The process is easy and safe to operate, and industrial production is easy.
- -
-
Paragraph 0022-0025
(2019/05/04)
-
- Synthesis of [13C3]-B6 vitamers labelled at three consecutive positions starting from [13C3]-propionic acid
-
[13C3]-labelled vitamers (PN, PL and PM) of the B6 group were prepared starting from [13C3]-propionic acid. [13C3]-PN was synthesized in ten linear steps with an overall yield of 17%. Hereby, higher alkyl homologues of involved esters showed a positive impact on the reaction outcome of the intermediates in the chosen synthetic route. Oxidation of [13C3]-PN to [13C3]-PL was undertaken using potassium permanganate and methylamine followed by acid hydrolysis of the imine derivative. [13C3]-PM could be prepared from the oxime derivative of [13C3]-PN by hydrogenation with palladium.
- Bachmann, Thomas,Rychlik, Michael
-
-
- Synthesis of 4-methyl-5- [...] method
-
The invention discloses a method for synthesizing 4-methyl-5-alkoxyl oxazole, the method comprises a step b or a step a to the step b in a synthesis route, the synthesis route is shown as the follows, the step a is characterized in that 1,1-dialkoxy acetone is reacted to acetyl halides to generate 1-alcoxyl-1-halogenated acetone; the step b is characterized in that 1-alcoxyl-halogenated acetone is performed a cyclization reaction with methanamide to generate 4-methyl-5-alkoxyl oxazole; wherein the substituted group R is C2-C12 alkyl, and the substituted group X is a halogen element. The synthetic method has the advantages of simple operation, easy acquisition and small toxicity of raw material, high reaction yield and less pollution, and the industrial large production requirement can be satisfied.
- -
-
Paragraph 0042; 0043
(2017/01/26)
-
- Improved oxazole Method for the Practical and Efficient Preparation of Pyridoxine Hydrochloride (Vitamin B6)
-
Vitamin B6, a well-studied vitamin B, has been synthesized using an oxazole method for the past 20 years. The oxazole method provided 56.2% overall yield but also generated safety, environmental, and health problems, such as using toxic benzene as solvent and unstable, corrosive, and pollutive HCl and POCl3 as reagents. To use the same equipment but the least amount of toxic agents, we developed new reaction conditions for the early steps. For example, we successfully replaced toxic HCl/benzene conditions with NaHSO4/PhCH3 conditions and also developed a novel and efficient dehydrating agent trichloroisocyanuric acid/Ph3P/Et 3N to synthesize the key intermediate 5-butoxy-4-methyl oxazole, instead of using phosphorus oxychloride. These improvements resolved safety, waste avoidance, and workup issues that plagued the previous methodologies. Our process comprised six easy synthetic steps and generated vitamin B6 with 99.4% purity in 56.4% overall yield.
- Zou, Ye,Shi, Xiangjun,Zhang, Genbao,Li, Zhenhua,Jin, Can,Su, Weike
-
p. 1498 - 1502
(2014/01/06)
-
- Peroxisome proliferator-activated receptor-γ mediates the anti-inflammatory effect of 3-hydroxy-4-pyridinecarboxylic acid derivatives: Synthesis and biological evaluation
-
Seven 3-hydroxy-4-pyridinecarboxylic acid derivatives (HPs), aza-analogues of salicylic acid and structurally close to other potent inflammatory pyridine compounds such as aminopyridinylmethanols and aminopyridinamines, were synthesized, and their anti-inflammatory activity was evaluated. The synthesis was performed by adopting a general procedure involving an intramolecular Diels-Alder cycloaddition of oxazoles with acrylic acid to form various substituted pyridinic acids. The newly synthesized HPs did not exhibit cytotoxic activity on human monocytes-derived macrophages at concentrations up to 10 2 μM. Anti-inflammatory activity of the compounds was screened in vitro by evaluating the capability to inhibit cytokines release from lipopolysaccharide (LPS) stimulated human macrophages. 3-Hydroxy-1-methyl-4- pyridinecarboxylic acid (24) was found to be the most active HP. At 10 μM concentration, HP 24 reduced LPS-induced and nuclear factor-κB activation and cyclooxygenase-2 expression, while increased intracellular reactive oxygen species generation and peroxisome proliferator-activated receptor (PPAR-γ) mRNA transcript level. Indeed, pre-treatment of LPS-exposed human macrophages with PPAR-γ specific antagonist completely prevented HP 24-induced TNF-α and IL8 down regulation, demonstrating that the PPARγ pathway is mandatory for the HP 24 anti-inflammatory effect. Finally, daily treatment with HP 24 ameliorated the outcome of DSS-induced colitis in mice, significantly reducing colonic MPO activity and IL-1β tissue levels.
- Brun, Paola,Dean, Annalisa,Di Marco, Valerio,Surajit, Pathak,Castagliuolo, Ignazio,Carta, Davide,Ferlin, Maria Grazia
-
p. 486 - 497
(2013/06/04)
-
- NMR studies of the protonation states of pyridoxal-5′-phosphate in water
-
We have measured the 13C NMR spectra of the cofactor pyridoxal-5′-phosphate (vitamin B6, PLP) at 278 K in aqueous solution as a function of pH. By 13C enrichment of PLP in the C-4′ and C-5′ positions we were able to measure spectra down to pH 1. From the dependence of the 13C chemical shifts on pH, the pKa values of PLP could be determined. In particular, the heretofore uncharacterized protonation state of PLP, in which the phosphate group as well as the pyridine ring and the phenolic groups are fully protonated, has been analyzed. The corresponding pKa value of 2.4 indicates that the phosphate group is solely involved in the first deprotonation step. The 15N chemical shifts of the pyridine ring of PLP published previously are in good agreement with the new results. These shifts contain information about the tautomerism of the different protonation states of PLP. The implications of these findings for the biological function of PLP are discussed.
- Chan-Huot, Monique,Niether, Christiane,Sharif, Shasad,Tolstoy, Peter M.,Toney, Michael D.,Limbach, Hans-Heinrich
-
experimental part
p. 282 - 289
(2010/08/19)
-
