Butofilolol

Cafide,Clin Midy,France,1982

Butofilolol is a beta-blocker drug and used for treating hypertension.

ChEBI: Butofilolol is an aromatic ketone.

(a) 5-Chloromethyl-3-tert-butyl-2-(2-hydroxy-5-fluorophenyl)oxazolidine: 5- Fluorosalicylaldehyde (1.4 g, 0.01 mol) is dissolved in anhydrous benzene (20 ml) in the presence of a crystal of p-toluenesulfonic acid in a Dean-Stark apparatus. 1-Chloro-2-hydroxy-3-tert-butylaminopropane (2.08 g, approximately 1 equivalent, purity 75%) is then added within a period of 10 hours in portions of 250 mg at a time at the reflux temperature of benzene and the mixture is allowed to stand overnight. An insoluble substance is precipitated on addition of ether after which the solution is filtered, concentrated and distilled. A fraction is obtained having a boiling point of 118°-123°C/10-3 mm of mercury. A mixture of 1.03 g (yield 43%) of isomeric oxazolidines is obtained which solidifies. This is crystallized once from hexane. Melting point 75°-78°C.
(b) 8-Aza-4,9-dioxa-11l-fluoro-8-tert-butyl-2,3-benzobicyclo[4.2.1]octane: The product of the previous stage (620 mg) is dissolved in anhydrous dimethylformamide (10 ml) and two quantities each of 300 mg of 50% sodium hydride is added within 2 hours. The mixture is then left for 24 hours at 25°C while being stirred mechanically and is then heated for 2 minutes on a water bath (80°-90°C). The mixture is poured into water, the product extracted with ether, the ethereal extract dried over anhydrous sodium sulfate and the organic phase then concentrated and filtered through a short column of activated alumina. A mixture of light petroleum and diethyl ether (75:25) is used to elute 186 mg of pure product from the column. Melting point 85°- 86°C (after recrystallization from diisopropyl ether).
(c) 1-(2-Formyl-4-fluorophenoxy)-2-hydroxy-3-tert-butylaminopropane: The compound obtained as described above (50 mg) is dissolved in a solution of 1N hydrochloric acid (0.5 ml). The mixture is then heated on a water bath (80°-90°C) for several hours. After complete hydrolysis, which requires approximately 8 hours, the mixture is poured into an excess of water which has been basified, the solid base thus formed is extracted with ether, dried and recrystallized from diisopropyl ether. Melting point 103°-105°C.
(d)1-[2(1-Hydroxybutyl)-4-fluorophenoxy]-2-hydroxy-3-tert-butylaminopropane: To a solution of propylmagnesium bromide prepared from 195 mg (8.1 X 10-3 mol) of magnesium, 1.08 g (8.1 X 10-3 mol) of bromopropane and a crystal of iodine in 10 ml of anhydrous diethyl ether under nitrogen is added a solution of the previously prepared aldehyde (197 mg, 0.73 x 10-3 mol) in 4 ml of an ether/tetrahydrofuran mixture (1:3 by volume) and the mixture is heated to reflux for 70 minutes. The mixture is poured into water, extracted with diethyl ether, dried over anhydrous sodium sulfate and 208 mg of an oil which is homogeneous, as shown by thin-layer chromatography, is isolated.
(e) CM 6805 (Butofilolol): The previously prepared base (200 mg, 0.66 X mol) is dissolved in purified acetone (8 ml). A drop of sulfuric acid solution (prepared from 35 ml of concentrated sulfuric acid and 65 ml of water) is added and the mixture heated on a water bath for 1 minute. When the solution has cooled to 5° to 10°C a solution of chromic acid (66 mg, 1 equivalent) dissolved in 2 ml of the same acid solution is quickly added and the resulting mixture is stirred while cold. The mixture is then poured into a saturated solution of sodium carbonate, the acetone is evaporated under reduced pressure on a water bath, and the organic phase is extracted with diethyl ether. After drying and evaporating the solvent an oil is obtained (172 mg) all of which solidifies. Recrystallization is carried out from diisopropyl ether. 122 mg of CM 6805 is obtained (yield 61%). Melting point 88°-89°C.

Beta-adrenergic blocker