IL26810A - Benzofuran derivatives and process for the manufacture thereof - Google Patents

Description

PATENTS AND DESIGNS ORDINANCE SPECIFICATION derivatives and process for manufacture thereo ROCHE a Swiss of do hereby declare the nature of this invention and in what manner the same is to be to particularly described and ascertained in and by t following statement The present invention is concerned with novel benzofuran derivatives and a process for the manufacture The novel benzofuran derivatives provided by the invention are compounds of the general wherein is B is bromine o a in which R represents a lower or A and B form together 1 2 an R an group and R stands hydrogen or a or or a group and acid addition salts of those compounds in which B a group It will be appreciated that the term alkyl1 is used in this to mean and chain alkyl groups containing a relatively low number of carbon atoms and ter One class of compounds provided by the invention comprises those compounds of formula I in which S and R have the same meaning as An interesting class of derivatives of formula I are those in which R stands for a or especially a and acid addition salts An especiall interesting class of derivatives by the invention comprises those compounds of formula I in which R represents the isopropyl and acid addition salts According to the process provided by the the novel derivatives aforesaid are manufactured by reacting a hydrin of the general formula wherein and have the significance given earlier and X is chlorine or in the presence of an with an amine of the formula wherein R has the significance given by reacting an epoxide of the general formula wherein and have the above with an amine of the formula IV converting the reaction product into an acid addition The halohydrin starting materials of formula II may be obtained by reducing a haloketone of the general formula wherein and X have the above with an borohydride or with aluminium isopropoxide in The reduction of a haloketone material of formula V with an borohydride sodium may conveniently be carried out at a temperature of or belo at The reduction is conveniently carried out in the presence of a solvent which is inert under the conditions of the and aqueous dioxan have been found to be suitable for this The reduction of the haloketone materials of formula V with aluminium isopropoxide in isopropanol is preferably carried out The epoxide starting materials of formula III may be This dehydrohalogenation may conveniently be carried out by treatment at room temperature with an hydroxide potassium dissolved in a alkanol or suspended in a organic solvent such as The haloketones of formula V can be for by converting a substituted salicylaldehyde of the formula wherein and have the significance given into an reacting this salt with ne and chlorinating or brominating the resulting substituted The conversion the substituted aldehyde of formula VI into an salt may veniently be carried out by treatment with an droxide in a ethanolic potassium The reaction of the salt with may conveniently be carried out in the presence of an inert organic solvent a such as The chlorination is conveniently carried out by treatment with sulfuryl chloride in an inert organic solvent but the is conveniently carried out using cupric bromide in a mixture of ethyl acetate and The substituted salicylaidehydes of formula VI wherein represents substitution f r xam either b convertin the corresponding salicylaldehyde in which is absent into its allyl ether and subjecting this ether to a CLAISEN rearrangement or by reacting the appropriately substituted with dichloromethylmethyl ether and titanium tetrachloride in methylene chloride or using hexamethylenetetramine under the conditions of a DUFF The aldehyde of formula VI can be for example by converting salixylaldehyde into its allyl subjecting this ether to CLAISEN converting the resulting into its allyl ether and subjectin the resulting ether to a CLAISEN An interesting clas of of V comprises those wherein represents a or or or especially Another interesting class of are p those in which R represents diallyl Especially interesting are and The reaction of a halohydrin of formula II with an amine of formula IV ma conveniently be carried out by heating the halohydrin with at least one of the amine at an vated temperature in the presence of a suitable Suitable agents for pyridine preferably preferably carried out using at least two of amine for each of heating be out in presence of an inert organic solvent a such as ethanol or except where solution of the agent is this is not The heating may also be carried out in an and this procedure is advantageous volatile amines are Isopropyl amine is especially interesting amine of formula The reaction an epoxide of formula III with an amine of formula IV may be carried out by heating the epoxide with the amine at an elevated temperature It is preferred to use an excess of the amine in this the reaction may be carried out in an inert organic solvent at room temperature in the presence of boron trifluoride The compounds of formula I contain an asymmetric carbon atom and occur in the form of a This racemate can be separated into its optical isomers in accordance with methods known per for by fractional zation of the The acid addition salts provided by the invention are formed with inorganic acids hydrochloric bromic sulphuric acid and phosphoric and with organic acids acetic tartaric maleic The compounds of formula I and their acid addition salts are useful as adrenergic blockin agents in the treatment cardiac such as cardiac arrhythmi and angina The compounds of formula I wherein R2 allyl are also useful in that they can be readily converted into the corresponding compounds in which Rl R2 represents a propyl group and into ves of formula I The novel by invention may be used as medicaments in the form of pharmaceutical preparations which contain them in admixture with a compatible pharmaceutical The pharmaceutical preparation may be made up enteral or parenteral Solid preparations for oral include capsules and the carrier being inorganic or organic lactose or Additives such as magnesium stearate a may also be Liquid preparations for oral administration include and suspensions and the diluents commonly used in pharmacy wa er and petroleum may be present in such The liquid preparations may take the form of sterile aqueous or suspensions or Polyoxyethyleneglycols and vegetable oils are useful suspending Emulsifying dispersing agents and other adjuvants may also be The pharmaceutical preparations may be submitted to the usual pharmaceutical operations such as sterilization and may be compounded with other therapeutically valuable The following Examples illustrate the process provided by the Example 1 The preparation of the A solution of 243 g of in 1000 ml of ethanol was treated at with stirring with a solution of g of potassium hydroxide in 500 ml of 146 g of were added in the course of hour with stirring to the resulting yellow potassium The temperature of the mixture rose to The mixture was subsequently stirred at for 20 after which time water was added and most of the ethanol was removed under reduced The residue was extracted three times with ether the combined extracts were washed with water and dried over sodium Distillation of the solution gave 184 g of of boiling point Crystallization from isopropanol gave 144 g of colourless plates of melting point 115 g of were dissolved in 690 ml of chloroform and the solution was treated dropwise with stirring in the course of hour with ml of sulfuryl The mixture was slowly heated to the reflux temperature the course of 20 and heated under gentle reflux for After the mixture was poured to ice combined extracts were washed with sodium carbonate solution and water and dried oyer sodium The dried solution was filtered and evaporated to give 61 g of which melted at after crystallization from a small volume of Recrystallization from petroleum ether range gave g of pure material of melting point g of in 167 ml of dioxan and 42 ml of water were treated portionwise with stirring over the course of hour at with 4 g of sodium After several hours at the solvent was removed under reduced water was added to the residue and the mixture was extracted three times with There resulted 6 g of crude benzofuran which did not The 25 g of crude furan in 60 ml of ethanol were heated at reflux for 24 hours with g of isopropyl The solvent was then removed and residue was dissolved in dilute hydrochloric The solution was washed three times with ether and made basic with sodium hydroxide was extracted with ether and converted into the hydrochloride by means of ethereal hydrochloric Example 2 The preparation of the starting g of g of methylenetetramine and g of paraformaldehyde were melted together 15 ml of glacial acetic acid were added with stirring over 1 hour to the melt and the temperature of the mixture was raised to 4 ml of concentrated sulfuric acid were added over a period then the mixture was poured into of hot water and steam distilled until no more oil came over in the The distillate was extracted twice with chloroform and the extracts were washed with water and dried over anhydrous sodium The dried solution was filtered and the chloroform was removed from the filtrate under reduced The residual oil was distilled to give g of as a pale yellow oil of boiling point A solution of g of potassium hydroxide in ml of ethanol was added dropwise at room temperature to a stirred solution of g of 350 ml of ethanol to give a yellow solution of the corresponding potassium g of were added dropwise over hour and the mixture obtained was stirred at room temperature for 24 then poured into litres of water and extracted three times with The combined extracts were washed successively with dilute sodium hydroxide solution and water and dried over anhydrous sodium The dried solution was filtered and the chloroform was removed from the filtrate under reduced The residual viscous oil was distilled to give a yellow oil of boiling point which solidified on Crystallization from ethanol gave g of as white prisms of melting point 71 g of sulfuryl chloride were added with stirring over 20 minutes to g of in 500 ml of The mixture was then heated under reflu for 3 cooled and poured on to The layers were separated and the aqueous layer was washed with The combined washings and form layer were washed with sodium solution and then with water and dried over anhydrous sodium The dried solution was filtered and the chloroform was removed from the filtrate under reduced The solid residue was crystallized from ethanol to give g of as crystals of melting point g of benzofuran were dissolved in a mixture of 120 ml of dioxan and ml of water and the solution was cooled to in g of sodium borohydride were added in portions with stirring for 3 The was then removed under reduced pressure and the residue diluted with water and extracted three times with The combined extracts were washed with water and with brine and dried over sodium The dried solution was filtered and the filtrate was evaporated under reduced pressure to give 12 g as a pale yellow viscous The This crude 2 10 benzofuran was heated under reflux for 24 hours in ethanol with 18 g of isopropyl The mixture was then cooled and the ethanol and excess isopropyl amine were removed under reduced The residual oil was dissolved in dilute hydrochloric acid and the solution was 15 washed twice with ether and made basic with sodium hydroxide The liberated oil was extracted with two portions of The combined extracts were washed with water and with brine and dried over sodium The dried solution was filtered and the ether was evaporated from the filtrate under 20 reduced On cooling to the residual oil became Recrystallization from cyclohexane gave g of furan as a white powder of melting point This was shown by chromatography to be a single substance 25 and by nuclear magnetic resonance spectroscopy to be the desired The free base was converted into the melting point Example 5 A The preparation of the starting material A solution of g of potassium hydroxide in ml ethanol was added to a solution of 176 g of in 700 ml of After stirring the mixture at for g mol of were added dropwise with stirring over the temperature rising to The mixture was stirred at 20 after which time part of the ethanol was removed under reduced pressure and about ml of water were The mixture obtained was extracted with ether and the extracts were washed twice with and dried over anhydrous sodium The dried solution was evaporated to a syrup which was distilled to give a main boiling at The thus obtained was redistilled and boiled at A solution of 12 g of benzofuran in 60 ml of chloroform was cooled to and ml of sulfuryl chloride were added dropwise thereto over a period of 10 minutes with The reflux temperature over a period of hour and kept there for After this the mixture was poured on to ice and extracted three times with The tracts were washed twice with sodium carbonate solution and once with dried over anhydrous sodium filtered and evaporated to a syrup which was first lized from isopropanol and then from petroleum ether range to give as creamy prisms of melting point Analysis indicated attack of the allyl double bonds by chlorine and the several recrystallizations required to remove resulting impurity caused some decrease in A solution of g of in 0 ml of dioxan and 8 ml of water was cooled to At this g mol of sodium borohydride were added with stirring over The mixture was stirred for a further hour at and for hours at The solvent was then removed under reduced pressure and 0 of water were The mixture was extracted three times with and the extracts were washed once with water and dried over anhydrous sodium The dried extracts were evaporated to yield in the form of a yellow mol of isopropanol were boiled reflu for 17 The and excess isopropyl amine were then removed under reduced pressure and the residue was acidified with dilute hydrochloric V7ater was added until the oily chloride which had separated out Any neutral material remaining was removed by extracting three times with then aqueous solution was basic with sodium hydroxide solution and extracted three times with The extracts washed twice dried over anhydrous sodium filtered and evaporated to give g a basic This was not thin indicated the h and o The as chromatographed on alumina to yield g of material by thin layer chromatography to solely of from petroleum ether range at gave of melting point The crystalline base was converted into the hydrochloride which was crystallized from a large volume of ethyl as colourless prisms of melting point nolj of were heated under reflux in 100 a mixture with 12 of amine 24 cooled was evaporated to the was made basic dilute hydroxide solution extracted twice with ether extracts and with saturated sodium chloride solution ried anhydrous sodium T e sodium sulphate was the filtrate reduced residual oil was dissolved in hydrogen chloride was added the resulting hydrochloride iron as white crystals of point e used as the starting material can be obtained as of e wit stirring a period of minutes at a temperature of to a solution of g of ml of re was stirred at for 2 evaporated under reduced pressure the residual was partitioned and aqueous and layers layer with ether and the combined ether with saturated was then the filtrate od at reduced 140 dry and to a stirred of ml of at a period of e then at filtered the filtrate was finally washed with saturated chloride solution dried over anhydrous sodium sulphate was removed the pressure and the residual oil give of boiling point s C pf mm heated under in 100 ml of with g of i reduced the residue basic with dilute sodium solution and ext acts were washed with and dried over anhydrous sodium removed by filtrate was evaporated under reduced the was dissolved in sad S of acid and prolonged at fom gave of this as white solid of melting point She as the starting material can prepared s A of g of potassium was over a period of minutes at to a stirred solution of g 0 of ml of were added over a period of 50 minutes to the stirred stirring a further evaporated o under reduced pressure and residue partitioned between water and organic phase was washed successively with wate dilute water and saturated sodium chloride dried over anhydrous sodium sulphate and evaporated at reduced residual oil was fractionally distilled to yield 8 g of of boiling colourless g of were added in one portion to stirred 6 of 21 g of 7 ran in 200 of dry S at mixture for 2 hours during a heav precipitate of trimet 10 bromide The mixture was poured into water 11 extracted twice methylene di The 12 extracts washed successively with 13 saturated sodium bicarbonate water and 14 saturated chloride and then dried 15 over anhydrous sodium Removal of the solvent 13 gave a viscous oil which solidified on cooling to V but which defied all attempts at crystallisation and 18 which decomposed on attempting The inf ared and nuclear magnetic resonance spectra 20 of the product satisfactory the 21 subsequent reaction was carried out with this 22 of the 23 aa prepared as in the 24 preceding paragraph were dissolved 100 ml of ethanol 23 and 2 g of ydride were added portionwise to the stirred solution over a period of 27 at She Mixture was stirred at for 28 was removed by evaporation reduced so pressure and the residue was partitioned between water and phases separated the aqueous phase was extracted with combined ethereal solutions were with water and saturated sodium chloride solution and dried over anhydrous sodium sodium sulphate by filtration and the removed by evaporation unde reduced pressure to yield 18 g as a mobile yellow The following Examples illustrate the manner in which the novel derivatives provided by the invention may be made up into pharmaceutical Example 6 Tablets each 25 of 114 of lactose mg of corn starch mg of pregelatinized corn starch and mg of calcium stearate and having weight of mg were prepared by the active material with the corn starch and pregelatinized corn starch i in a suitable passing mix through a returning the mixture to the moistening it with water so as to form a thick passing the moist mass through a drying the moist granules on trays returning the dried granules to the adding the calcium mixin well and compressing the granulate at a tablet weight of 200 mg using standard diameter concave Example 7 Tablets containing hydrox hydrochloride and otherwise identical to those described in Example 6 were prepared as set forth in said Example Example Capsules each containing mg of mg of mg of starch and mg of talc and having a total net weight of mg were prepared by mixing the active material with the lactose and starch in a suitable passing the mix through a comminuting returning the mixture to the adding the blending thoroughly and filling the ing powder into hard shell gelatin capsules on a Example 9 containing mg of hydrochloride and otherwise identical to those described in Example β were prepared as set forth in said Example insufficientOCRQuality

Claims (1)

1. particularly ana the nature of our said invention and in manner the same is to be we declare that what we claim Benzofuran compounds of the general formula wherein A is B is bromine or a group in whieh R represents a lower alkyl or A and B form together 1 2 an R stands for an group and R stands for hydrogen or a or or a Benzofuran compounds according to Claim 1 having the general formula 1 2 in which X is chlorine or and R and R have the same meaning as in Claim Benzofuran compounds according to Claim having the general formula wherein R and R have the same meaning as in Claim Benzofuran compounds according to Claim the 1 formula 2 in which R and R have the same meaning as in Claim 1 and acid addition salts Benzofuran compounds according to Claim wherein 2 represents an allyl group in position and acid addition salts Benzofuran compounds according to Claim wherein radical R represents a or and acid addition salts benzofuran and acid addition salts f and acid addition salts benzofuran and acid addition salts Benzofuran compounds according to any of Claims 4 to 9 and acid addition salts substantially as described herein with reference to Examples 1 to for the manufacture of benzofuran compounds of formula II in Claim wherein a haloketone of the formula in which X is chlorine or bromine and and have the same meaning as in Claim 1 is reduced with an A process for the manufacture of benzofuran compounds of formula III in Claim wherein a benzofuran compound of formula II in Claim 2 is dehydrohalogenated by treatment with an alkali metal hydroxide dissolved in a lower alkanol or suspended in a organic A process for the manufacture of benzofuran compounds according to Claim wherein a benzofuran compound of formula II in Claim 2 is reacted in the presence of an with an amine of the formula in which has the same meaning as in Claim 1 if the reaction product is converted into an acid addition A process for the manufacture of benzofuran compounds according to Claim wherein a benzofuran compound of the formula III in Claim 3 is reacted with an amine of the formula IV in Claim 13 if the reaction product is converted into an acid addition Processes according to Claim 13 or wherein in the compounds of formula II or III used as starting materials 1 stands for an group and represents a or Processes according to Claim 13 or wherein in the compounds of formula II or III used as starting R2 represents a lower alkyl group or an allyl group in position Processes according to any of Claims 13 to wherein an amine startin material of formula IV in Claim 13 is used as a in which R represents the isopropyl Processes the manufacture of benzofuran compounds according any of Claims 1 to substantially as described herein with reference to the compounds according to an of Claims 1 to when prepared by the processes according to any of Claims 11 to Pharmaceutical compositions having adrenergic blocking containing as an active ingredient a benzofuran compound according to any of 4 to 10 or an acid addition salt 1970 and acid addition salts For the Applicants PARTNERS I insufficientOCRQuality