Abstract:A general synthesis of selectively 6‐(trifluoromethyl)‐substitued 2(1H)‐pyridinones is described. Further transformation of one of these compounds leads to the new CF3‐containing potassium‐channel openers 2a and 2b.
“…3-Cyano-6-methyl-4-trifluoromethyl-2(1 H )-pyridone, 19. Colorless crystals of 19 (65 mg, 0.32 mmol, 64%), mp 232−233 °C (lit. 14a, mp 232−234 °C, lit. 14b,d mp 234 °C), were obtained after dissolving 5j (93 mg, 0.5 mmol) in trifluoroacetylacetone 18 (2 mL) and keeping the mixture under air for 48 h at rt. Anal.…”
The thioenols derived from cyanomonothiocarbonylmalonamides and a cyanodithiocarbonylmalonamide were found to be very reactive species. They react under a variety of conditions such as crystallization, reaction with several carbonyl compounds, and reactions with another thioenol molecule to give a variety of products, mostly heterocycles, including substituted 2,3-dihydroisothiazole-3-ones and 3-thione, 2-substituted methylenethiazoles, 3,4-dihydro-1,3-thiazine-4-ones and 4-thiones, divinyl sulfides, a 1,2-dithiolane radical, and a 3,7-diaza[3.3.0]bicyclooctane derivative. Mechanisms suggested for these reactions include radical mechanisms, nucleophilic substitutions, and condensations.
“…3-Cyano-6-methyl-4-trifluoromethyl-2(1 H )-pyridone, 19. Colorless crystals of 19 (65 mg, 0.32 mmol, 64%), mp 232−233 °C (lit. 14a, mp 232−234 °C, lit. 14b,d mp 234 °C), were obtained after dissolving 5j (93 mg, 0.5 mmol) in trifluoroacetylacetone 18 (2 mL) and keeping the mixture under air for 48 h at rt. Anal.…”
The thioenols derived from cyanomonothiocarbonylmalonamides and a cyanodithiocarbonylmalonamide were found to be very reactive species. They react under a variety of conditions such as crystallization, reaction with several carbonyl compounds, and reactions with another thioenol molecule to give a variety of products, mostly heterocycles, including substituted 2,3-dihydroisothiazole-3-ones and 3-thione, 2-substituted methylenethiazoles, 3,4-dihydro-1,3-thiazine-4-ones and 4-thiones, divinyl sulfides, a 1,2-dithiolane radical, and a 3,7-diaza[3.3.0]bicyclooctane derivative. Mechanisms suggested for these reactions include radical mechanisms, nucleophilic substitutions, and condensations.
“…This route is attractive because it is short, uses readily available raw materials, and involves standard “wet” chemistry. The route has been reported for the synthesis of pyridones 18 , but the onward conversion to the pyridone 1 has hitherto not been reported in the literature. 4 The trifluoroacetic anhydride (TFAA) route…”
Three routes to 6-(trifluoromethyl)pyrid-2-one involving de noWo synthesis of the pyridine ring have been investigated which would potentially allow rapid semi-technical scale manufacture. A route starting from ethyl 4,4,4-trifluoroacetoacetate (β-keto ester route) has been demonstrated. Development of the route was attempted; however, poor yields at a number of stages and scale-up difficulties made this route unattractive for commercial use. A four-stage route starting from trifluoroacetic anhydride and an alkyl vinyl ether (TFAA route) has been developed which gives good yields and productivity for all stages. The final stage of this route is a difficult decarboxylation of a nicotinic acid derivative, but an 80% yield of the required pyridone with a purity of >99.5% could be achieved without a separate purification stage. The route was scaled up to 2000 L, and several hundred kilograms of product was prepared.
“…The 3-cyano-6-trifluoromethyl-2(1H)pyridone (2) [14] was prepared by acylation of vinyl butyl ether in pyridine at RT, followed by reaction with cyanoacetamide in presence of sodium ethoxide in ethanol. The 2(1H)pyridone (2) was reacted with a-bromoethylacetate in acetone using potassium carbonate as base and potassium iodide as catalyst and obtained selectively O-alkylated product, that is, ethyl 2-(3-cyano-6-(trifluoromethyl)pyridine-2-yloxy) acetate (3) [15].…”
The 3‐amino‐6‐(trifluoromethyl)furo[2,3‐b]pyridine‐2‐carbohydrazide (5) was prepared from 3‐cyano‐6‐trifluoromethyl‐2(1H)pyridone (2) in series of steps via selective O‐alkylation, Thorpe–Ziegler cyclization followed by reaction with hydrazine hydrate. The 2‐carbohydrazide (5) was further reacted with aliphatic acids under different reaction temperatures to form a series of novel N‐acylfuro[2,3‐b]pyridine‐2‐carbohydrazide (6) and pyrido[3′,2′:4,5]furo[3,2‐d]pyrimidine derivatives (7). All the compounds 6 and 7 were screened for cytotoxic activity against breast carcinoma MD Anderson‐Metastatic Breast (MDA‐MB) 231 (aggressive) cell lines at 10 µM concentration. Compounds 6a, 6b, and 6c showed promising activity.
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