New method for the synthesis of thieno[2,3-d]pyrimidines

Abstract

The reaction of 5-formyl-4-thiocyanatopyrimidines with nitromethane was studied under various conditions. The reaction was found unexpectedly to proceed with closure of a thiophene ring to give thieno [2,3-d]pyrimidines. The use of ammonium acetate as the catalyst leads to a side reaction involving closure of an isothiazole ring to give isothiazolo [5,4-d]pyrimidines. X-ray diffraction crystallographic analysis was used to confirm the structure of thieno [2,3-d]pyrimidine.In a continuation of a study of 4-dialkyldithiocarbamoyl-5-nitropyrimidines and some of the chemical and physicochemical properties of these compounds [1], we investigated 4-thiocyanatopyrimidines, which have a nitroethylene group at C (5) .The properties of alkyl-and arylthiocyanates have been studied rather extensively since these compounds have high insecticidal activity [2]. The synthetic methods for thiocyanate derivatives are based, as a rule, on the reaction of the corresponding halides, sulfates, or sulfonates with ammonium or alkali metal thiocyanates [3,4]. 4,6-Dichloro-5-formylpyrimidines 1a,b were prepared according to reported procedures by the Vilsmeier formylation of 4,6-dihydroxypyrimidines with the concurrent replacement of the hydroxy groups by chlorine atoms [5,6].In the first stage, we synthesized 6-amino derivatives 2a-d by treating dichloropyrimidines 1a,b in dioxane with an aqueous solution of amine in the presence of an equimolar amount of acetic acid added to prevent the replacement of the second chlorine atom. The presence of the electron-withdrawing formyl group at C (5) permits us to replace the second chlorine atom in 6-amino-4-chloro derivatives 2a-d by a thiocyanato group by treating the corresponding chloro derivative with potassium thiocyanate in methanol or DMF. Thiocyanates 3a-d were obtained in high yield (Scheme 1).Since the lability of the chlorine atoms in 1a,b is less than in the analogous 5-nitropyrimidines, we were able to replace only one of the chlorine atoms by a thiocyanate group in 2-methylmercapto derivative 1b [7][8][9]. The reaction was carried out in methanol at 17°C and monitored by thin-layer chromatography. It proved necessary to stop this reaction when about half of the starting compound still remained in the reaction mixture since the reaction is complicated by the formation of a large amount of impurities. Dilution of the reaction mixture with water and recrystallization of the precipitate gave monothiocyano derivative 2e in 27% yield. __________________________________________________________________________________________

Preparation of 8‐Aza‐7‐deazaaristeromycin and ‐neplanocin A and Their 5′‐Homologs

“…Thus, beginning with the conversion of commercially available 4,6‐dihydroxypyrimidine to 5‐formyl‐4,6‐dichloropyrimidine ( 8 ) followed a literature procedure with slight modification . Aminolysis of 8 with dimethylamine afforded compound 9 , which was treated with sodium hydroxide to provide the ring‐cleaved product 10 . The synthesis to 7 was completed by ring closure of 10 (to 11 ) followed by treatment with formamide .…”

“…To this mixture, dimethylamine (40% aq., 11.4 mL, 100 mmol) was added, dropwise. Stirring was continued at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue purified by recrystallization from EtOH to give 4‐chloro‐6‐(dimethylamino)pyrimidine‐5‐carbaldehyde ( 9 ) (16.7 g, 90%) that was used directly in the next step. 1 H NMR (250 MHz, CDCl 3 ) δ 10.37 (s, 1H), 8.35 (s, 1H), 3.11 (s, 6H).…”

Machine Learning Models for Mycobacterium tuberculosis In Vitro Activity: Prediction and Target Visualization

“…Antituberculosis testing of these compounds with MIC 99 determination was made under the same conditions by standard resazurin assay; therefore, they can be compared with each other. The synthesis and activity against Mtb for many of these compounds has been previously published. − The activity data were both in MIC and MIC 99 values, which were defined as equivalent based on the criteria for Mtb activity from our previous published work. An additional step was used to quantify activity values that were ill defined (i.e., did not have an equal qualifier).…”

“…The majority of compounds have been previously published. − The determination of minimum inhibitory concentration (MIC) against M. tuberculosis strain H 37 Rv and M.…”

“…We have recently participated in the EU-funded public–private consortia New Medicines for Tuberculosis (NM4TB) and More Medicines for Tuberculosis (MM4TB) which ran from 2005 to 2016. , In the process of this work, >1000 molecules were synthesized and tested and some of these molecules were described in earlier publications. − We have now curated this data and used it as a test set for our machine learning models as well as a unique training set for regression model building and for prediction of the potential targets for these compounds. In the course of this work, we are now making this data publicly available.…”