OXADIAZOLYLACETONITRILES, THEIR PREPARATION AND USE

Abstract: Compounds of the formulae

Description: This invention provides 3-substituted-5-isocyanomethyl-1,2,4-oxadiazoles of formula XI and 5-substituted-3-isocyanomethyl-1,2,4-oxadiazoles of formula XII. EP-A-0201678 discloses 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole, but the novel compounds are the remainder of the given types in which the 5-substituent or 3-substituent, respectively is C₁₋₆ alkyl or C₃₋₆ cycloalkyl. The novel compounds are useful as intermediates in the preparation of the therapeutically-active quinazolines described and claimed in EP-B-0226282 (corresponding to Application No. 86307541.2 from which this application has been divided). The following description illustrates the preparation of particular examples of the invention. 5-(Ethyl or Methyl)-3-isocyanomethyl-1,2,4-oxadiazole The following compounds were synthesised from the appropriate ethyl esters, as described below, in a manner similar to that described in EP-A-0201678, for 3-formylaminomethyl-5-cyclopropyl-1,2,4-oxadiazole: 3-Formylaminomethyl-5-ethyl-1,2,4-oxadiazole. H-NMR (60 MHz, CDCl₃) (ppm): 1.4 (3H, t, J=8 Hz), 2.9 (2H, q, J=8 Hz) 4.55 (2H, s), 7.8 (1H, broad-NH), 8.25 (1H, s). 3-Formylaminomethyl-5-methyl-1,2,4-oxadiazole. H-NMR (60 MHz, CDCl₃) (ppm): 2.6 (3H, s), 4.6 (2H, d, J=3 Hz), 7.4 (1H, broad-NH), 8.25 (1H, s). These two compounds were then converted, as described below in a manner similar to that described in EP-A-0201678 for 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole which does not form part of the invention to 5-ethyl-3-isocyanomethyl-1,2,4-oxadiazole and 5-methyl-3-isocyanomethyl-1,2,4-oxadiazole. Both these were oils and were characterised by their IR stretching band at 2160 cm⁻¹. 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole a. 3-cyclopropyl-5-formylaminomethyl-1,2,4-oxadiazole . A solution of ethyl formylaminomethyl-carboxylate (150 mmol) and cyclopropyl carboxamide oxime (100 mmol) in 100% EtOH (100 ml) was charged with Na (200 mg) and a crushed molecular sieve (4A) (10 g). The mixture thus obtained was stirred and heated to reflux for 8 hours. The mixture was cooled to room temperature, filtered through filter aid and the filtrate was evaporated in vacuo. The oily residue was partitionated into a CHCl₃ phase which was dried with Na₂SO₄ and evaporated. b. 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole . A stirred solution of 3-cyclopropyl-5-formylaminomethyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH₂Cl₂ (100 ml) was charged dropwise with POCl₃ (60 mmol) at 0°C. The mixture was then left for 30 minutes with stirring at 0°C, whereafter a solution of Na₂CO₃ (60 mmol) in H₂O (50 ml) was added. The mixture was heated to room temperature, whereafter the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted and the solution was evaporated to give the title compound as an oil. The oil was processed without any further purification. The compound was characterized by its IR absorption band at 2160 cm⁻¹. 3-ethyl-5-isocyanomethyl-1,2,4-oxadiazole was prepared from 3-ethyl-5-formylaminomethyl-1,2,4-oxadiazole in a similar manner. IR: cm⁻¹: 2170. 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazol a. Formylaminomethyl-carboxamide oxime . 0.55 mmol of freshly liberated hydroxylamine dissolved in 370 ml methanol was added to 53.6 g (0.638 mmol) N-formylamino-acetonitrile. An ice bath was used to keep the temperature below 20°C during addition. The solution was allowed to stand at room temperature overnight, whereafter it was evaporated to give the title compound as pale crystals. Decomp. 104-110°C. b. 3-formylaminomethyl-5-cyclopropyl-1,2,4-oxadiazole A mixture of 35 ml ethyl cyclopropylcarboxylate , 20 g formylamino-methylcarboxamide oxime, 1 g sodium and 30 g of a crushed molecular sieve (4A) was refluxed in 300 ml abs. EtOH for 8 hours whereafter a further 1 g sodium was added The reaction mixture was filtered and the filtrate was evaporated. The dark oily residue was suspended in 300 ml CHCl₃, filtered and the filtrate was evaporated to give the title compound as an oil. H-NMR (60 MHz, CDCl₃) (ppm): 1.2 (4H, m), 2.8 (1H, m), 4.5 (2H, d, J=6Hz), 7.8 (1H, broad-NH), 8.2 (1H, s). c. 5-Cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH₂Cl₂(100 ml) was charged dropwise with POCl₃ (60 mmol) at 0°C. The mixture was then left for 30 minutes with stirring at 0°C, whereafter a solution of Na₂CO₃(60 mmol) in H₂O (50 ml) was added. The mixture was heated to room temperature, whereafter the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted and the solution was evaporated to give the title compound as an oil. The oil was processed without any further purification. The compound was characterized by its IR absorbtion band at 2160 cm⁻¹.

Claims: A 5-isocyanomethyl-1,2,4-oxadiazole of formula XI wherein R¹ is C₁₋₆ alkyl or C₃₋₆ cycloalkyl. A 3-isocyanomethyl-1,2,4-oxadiazole of formula XII wherein R² is C₁₋₆ alkyl or C₄₋₆ cycloalkyl. A compound of claim 1, wherein R¹ is ethyl or cyclopropyl. A compound of claim 2, wherein R² is methyl or ethyl.

Inventors: ENGELSTOFT, MOGENS, WAETJEN, FRANK, Wätjen, Frank 
Applicants: NOVO NORDISK A/S
Application year: 1986
Main classification: C07D271
IPC codes: A61P25, C07D498, A61K31, C07D513, C07D487, C07D413, C07D271