IL26795A - Benzofuran derivatives and process for the manufacture thereof - Google Patents

Description

•Jlllin ] ΠD T3inj"T 'TV PATENT ATTORNEYS · □ ' D J Q 3 'Dill) DR. REINHOLD COHN DR. MICHAEL COHN ISRAEL SHACHTER B.SC. mm κη¾ |Π3 TJtni"T n J Π I) IH. ' D Π .D.3 T D3 DJ I NI DJ " File CI 25474 PATENTS AND DESIGNS ORDINANCE SPECIFICATION Benzofuran derivatives and process for the manufacture thereof I/We p. HOPFI NI-iA ROCHE & CO., AKTIEHGESELLSCHAF , a Swiss company, of Basel, Switzerland do hereby declare the nature of this invention and in what manner the same is to be performed, to be particularly described and ascertained in and by the following statement :- RAN 4020/12 The present invention is concerned with novel benz derivatives and a process for the manufacture thereof.

The novel benzofuran derivatives provided by the invention are compounds of the formula wherein R represents a lower alkyl group, Rl represents - or 7-(chloro or bromo) or 5,7-di(chloro or bromo) substitution and R^ represents mono-, di- or tri(lower alkyl) substitution according to the availability of position or positions, and acid addition salts thereof. They are useful as adrenergic blocking agents [beta-type effects] in the treatment of cardiac disorders, such as cardiac arrhythmia and angina pectoris. The compounds of formula I are also useful in that they can be readily converted into the corresponding compounds in which R^" is absent and into 2,3-dihydro derivatives thereof.

■/It will be appreciated that the term 'lower alkyl' is used in this specification to mean alkyl groups containing a relatively low number of carbon atoms (e.g. methyl, ethyl, propyl, iso- propyl, butyl, sec. -butyl and tert. butyl). One interesting class of derivatives provided by the invention comprises those compounds of formula I in which R^ represents mono- or di(lower alkyl) substitution, (especially mono- or dimethyl or ethyl substitution), and a id addition salts thereof. Another interesting class of derivatives provided by the invention comprises those compounds of formula I in which R"^" represents bromo substitution, and acid addition salts thereof. An interesting lower-alkyl value for R is the isopropyl group.

According to the process provided by the invention, the novel derivatives aforesaid are manufactured by reacting a halo-hydrin of the general formula wherein R and 2 have the significance given earlier and X is chlorine or bromine, in the presense of an acid-binding agent, with an amine of the formula R-NH2 (IV) wherein R has the significance given earlier, or by reacting an epoxide of the general formula wherein and R have the above meanin , with an amine: of the formula IV above, and, if desired, converting the' reaction product into an acid addition salt.

. The halohydrin starting materials of formula II may be obtained by reducing a haloketone of the general formula wherein R , R and X have the. above meaning, with an alkali-metal borohydride or with aluminium isopropoxide in isopropanol.

The reduction of a haloketone material of formula V with an alkali-metal borohydride (suitably sodium borohydride) may conveniently be carried out at a temperature of 20°C or below (preferably at 0°-20°C). The reduction is conveniently carried out in the presence of a solyent which is inert under the conditions of the reduction. Lower-alkanols (e.g. ethanol) and aqueous dioxan have been found to be suitable for this purpose. at an elevated temperature.

The epoxide starting materials of formula III may he obtained by dehydrohalogenation of the halohydrins of formula II.

This dehydrohalogenation may conveniently be carried out by treatment at room temperature with an alkali-metal hydroxide (e.g.potassium hydroxide) dissolved in a lower-alkanol (especially methanol) or suspended in a non-polar organic solvent (e.g. benzene).

The. haloketones of formula V can be obtained, for example by chlorinating. or brominating. the appropriate lower alkyl-substituted phenol, transforming the chlorination or bromination product into the corresponding substituted salicylaldehyde, converting this substituted salicylaldehyde into an alkali-metal salt , condensing this salt with chloro-acetone and chlorinating or brominating the resulting substituted 2-acetyl-benzofuran. The chlorination and bromination of the lower alkyl-substituted phenol may suitably be carried out by passing gaseous chlorine or bromine through a solution of the phenol in an inert organic solvent (e.g. 'chloroform or acetic acid) at a temperature of from about 0°G to 20°0. The transformation of the chlorination or bromination product into the corresponding substituted salicylaldehyde can be carried out in accordance with methods known per se; for example, using dichloromethyl methyl ether and titanium tetrachloride in methylene chloride or using hexamethylenetetramine under the conditions' of a DUFF an alkali-metal salt ma conveniently be carried out using an alkali-metal hydroxide in a lower-alkanol. (e.g.ethanolic potassium hydroxide). The reaction of the alkali-metal salt with chloro-acetone is conveniently carried out in an inert organic solvent (e.g. a lower-alkanol such as ethanol) . The : chlorination of the reaction product is conveniently carried out by treatment with sulfuryl chloride and the bromination is conveniently carried ou by treatment with bromine in an inert organic solvent such as ether or cupric bromide in a mixture of ethyl acetate and chloroform. One interesting class of haloketone materials of formula V comprises those in which represents mono- or di (lower alkyl). substitution (especially mono- or dimethyl or ethyl substitution). Another interesting class of haloketones of formula V- comprises those in which It*- -represents bromo substitution.

The reaction of a halo ydrin of formula II with an amine of formula IV may conveniently be carried out by heating the halohydrin with at least 1 mol of the amine at an elevated temperature e.g. 50° - 100°C in the presence of a suitable acid-binding agent. Suitable acid-binding agents are, for example, alkali-metal carbonates, pyridine or, preferably, an excess of the amine itself. The reaction is accordingly preferably carried out using at least 2 mols of the amine for each mol of halohydrin. The heating may be carried out in the presence of an inert organic solvent such as ethanol but, except where solution of the acid-binding agent is necessary, this is not essential. The heating may also be carried out- in a when readily volatile amines are used.

The reaction of 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 (e.g. 50° -100°C). It is preferred to use an excess of the amine in this reaction. Alternatively, the reaction may be carried out in an inert- organic solvent (e.g. benzene) at room temperature in the presence of boron trifluoride etherate.

It will be appreciated that the compounds of formula I contain an asymmetric carbon atom and occur in the form of a stereoisomeric racemate. This racemate can be separated into its optical isomers in accordance with methods known per se; for example, by fractional crystallization of the salts.

The acid addition salts provided by the invention are those formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid) and with organic acids (e.g. acetic acid, tartaric acid, maleic acid, citric acid and toluenesulphonic acids).

The novel derivatives provided by the invention may be used as medicaments in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier. The pharmaceutical preparations may be made up for enteral (e.g. oral) or parenteral administration. Solid preparations for oral administration include tablets, pills, such as magnesium stearate (a lubricant) may also.be present.

Liquid preparations for oral administration include emulsions, solutions and suspensions and the diluents commonly used in pharmacy (e.g. water and petroleum jelly) may be present in such 5 preparations..The liquid preparations may take the form of sterile aqueous or non-aqueous solutions, suspensions or emulsions. Polyoxyethyleneglycols and vegetable oils are useful -/suspending, media. Emulsifyin agents, dispersing agents and other adjuvants may also be present. The .pharmaceutical preparations £0. may be submitted to the usual pharmaceutical operations such as sterilization and may be compounded with other therapeutically valuable materials.

The following Examples illustrate the process of the invention: Example 1 ' A) ' The preparation of the starting material: : A mixture of 50.25 g (0.25 mol) of 4-bromo-2,3-xylenol, 18.75 g of paraformaldehyde and 18.75 g of hexamethylenetetramine was melted to a paste. 75 ml of glacial acetic acid werd added to the stirred mixture over a period of 1 hour, the internal temperature being maintained at 100°C (bath temperature 125°C). 20.4 ml of. concentrated sulfuric acid were than added dropwise over a period of 2 hours, the internal temperature being maintained at 118° - 120°C (bath temperature 140°C). After addition was complete, the mixture was stirred for a further 0.25 hour at 118°C. The mixture was then poured into hot water an steam distilled. The aqueous distillate was extracted with chloroform and the extract was washed wit water and dried over sodium sulfate. Evaporation of the chloroform under reduced pressure yielded about 43 g of a yellow solid. This crude -bromo- . aldehyde 1 g (abou added -bromo-3» 42.2 (0.143 mol) of 2-chloroac.etyl-5-bromo-6,7-dimethyl^ benzofuran"were suspended in a mixture of 210 ml of dioxan and 35 ml of water and the suspension was cooled to 0°G. 3.99 g (0.072 mol + 2 #) of sodium borohydride were added portionwise at 0° - 5°C over a period of 0.5 hour and the mixture was stirred at 20°C for 3 hours. The solvent was then removed under reduced pressure and the residue was treated with water and extracted three times with ether The extracts were washed once with water and dried over anhydrous sodium sulphate. The dried solution was filtered and the filtrate was evaporated to give, a buff solid which was crystallized from benzene/(60° - 80°C petroleum ether) to yield 35.3 g of ^^ ^-chloro-l-hydro y^ethylT^S-bromo- 6,7-dimethyl-benzofuran in the form of colourless needles of melting point 100° - 102°C.

B) The process: A solution of 27.27 g (0.09 mol) of 2-^2-chloro-l-hydroxy)- ethyl7-5-bromo-6 7-dimethyl-benzofuran and 47 ml (0.54 mol) of isopropyl amine in 180 ml of isopropanol was heated under reflux for 24 hours (thin layer chroma ography of the reaction mixture showed the reaction product to be virtually uniform). The isopropanol and excess isopropyl amine were removed under reduced pressure and the solid residue vigorously shaken with excess 2-N aqueous sodium carbonate solution and filtered. The filter cake was shaken with water and again filtered, then shaken again with water, filtered once more, sucked dry and crystallized from ethanol to give a first crop of 16.6 g of 2T^"2-isopropylamino-l-hydroxy)-v Example 2 A) The preparation of the starting material: . A solution of 3.1 g (about 0.05 mol) of potassium hydroxide in 30 ml of ethanol was added dropwise with stirring at room temperature over a period of 10 minutes to a solution of 10.8 g (0.05 mol) of .5-bromo-3.-methyl-salicylaldehyde in 100 of ethanol. 4.8 g (0.05 mol + ) of chloro-acetone were added dropwise over a period of 0.25 hour to the resulting yellow solution. The mixture was stirred at room temperature for 20 hours,. then poured into 500 ml of water and extracted twice with chloroform.. The combined extracts were washed with dilute sodium hydroxide solution and then with water and dried over sodium sulphate. The solvent was recrystallized from ethanol to yield 9.3 g of 2-acetyl-5-bromo-7.-methyl-benzofuran as fine yellow needles of melting pfcint 122° - 123°0. 4.9 g (0.03 mol +·: 20 ) of sulfuryl chloride were added dropwise with stirring over.10 minutes to 7.6 g (0.03 mol) of 2-acetyl-5-bromo-r7-niethyl-benzofuran in 0 ml of. chloroform. The mixture was heated at gentle reflux for 3 hours, cooled and poured on to ice. The layers were separated and the aqueous layer was extracted with chloroform. The extract was combined with the organic layer, washed with'2-N sodium carbonate solution and then with water and dried over sodium sulfate. The dried solution was filtered and the filtrate was eva orated' under reduced pressure. The solid residue -was filtered and the filtrate was evaporated under reduced pressure. The solid residue was recrystallized from ethanol to yield 7.1 g of 2-chloroacetyl-5-bromo-7-methyl-benzofuran as fine yellow needles of melting point 134° - 137°C. 14.4 g (0.05 mol) of 2-chloroacetyl-5-bromo-7-methyl- benzofuran were dissolved in a mixture of 100 ml of dioxan and 20 ml of water and the solution was cooled to 0°C. 1.2. (0.025. mol + 20 ) of sodium borohydride were added portion- wise over a period of 0.5 hour and the mixture was stirred at room temperature for 2 hours. The dioxan was removed under reduced pressure and the residue was diluted with about 200 ml of water and extracted twice with ether. The combined extracts ium titative B) The process: The crude 2-^2-chloro-l-hydroxy)-ethyl7-5-bromo-7-methyl- benzofu an (about 0.05 mol) and 12 g (0.2 mol) of isopropyl amine were heated at reflux for 24 hours in 0 ml of ethanol.

The solvent and excess isopropyl amine were then removed under reduced pressure and the residual solid was partitioned between ether and dilute hydrochloric acid. The aqueous acidic layer was washed with ether, made, basic with dilute sodium hydroxide solution and extracted three times with ether. The combined ex sodium sulfate. Removal of the solvent left a brown solid ■which was crystallized. from petroleum ether (boiling range 60° - 80°C) to give 9.0 g of 2^^-isopropylamino-l-hydroxj)- j) j ethyl^-5-bromo-7-methyl-benzofuran as buff crystals of melting 5 point 120° -,130°C. Thin layer, chromatography showed the product to be a single substance and its structure was _ verified by nuclear magnetic resonance spectroscopy. 2-£2-_ ✓,■ Isopropylamino-l-hydroxy)-ethyl^-5-bromo-7-methyl-benzofuran hydrochloride melted at 158° - 159°C after recrystallization n . from ethanol/ether.

Example 3 A The preparation of the starting material: In a manner analogous to that described in the first paragraph of Example 2A, 3-bromo-5-methyl-salicylaldehyde was 5 reacted with chloro-acetone to give .2-acetyl-7-bromo-5-methyl- benzofuran as cream-coloured crystals of melting point 85°C (after crystallization from ethanol) .

In a manner analogous to that described in the second paragraph of Example 2A, from 2-acetyl-5-methyl-7-bromo-benzo-0 furan there was obtained 2-chloroacetyl-7-bromo-5-methyl-benzO' furan as yellow prisms of melting point 131° - 133°C (after recrystallization from ethanol) . 2-Chloroacetyl-5-methyl-7-bromo-benzofuran was reduced in a manner analogous to that described in the third paragraph ~>/V of Example 2A to give ^^^-chloro-l-hydroxyj-ethy-lj^-methyl- 7-bromo-benzofuran as a pale yellow oil. 136° - 138°G after recrystallization from ethanol/ether.

Example 4 , A) The preparation of the starting material; In a manner analogous to that described in the first paragraph of Example 2A, 3> 5-dibromo-6^methyl-salicylaldehyde was reacted. ith chloro-acetone to give 2-acetyl-4-methy1-5,7- dibromo-benzofurari in the form of white prisms of melting point 162° - 163°G (after recrystallization from ethanol) .

In a manner analogous to that described in the second 2 A, from 2-acetyl-4-methyl-5»7-dibromo- 2-Chloroacetyl-4-methyl-5,7-dibromo-benzofuran was reduced in a manner analogous to that described in the .third > paragraph of Example 2 A to give 2-^2-chloro-l-hydroxy)-ethylJ- 4-methyl-5, 7-dibromo-benzofuran. benzofuran hydrochloride was obtained as white crystals of melting point 200° - 201°C after crystallization from ethanol/ ether. ■ · ,* ■ · Example 5 . A) The preparation of the starting material: In a manner analogous to that described in the first paragraph of Example 2A, 3-ethyl-5-bromo-salicylaldehyde was reacted with chloro-acetone .to give 2-acetyl-5-bromo-7-ethyl- benzofuran as yellow crystals of melting point 68° - 70°C.

In a- manner analogous to that described in the second paragraph of Example 2A, from 2-acetyl-5-bromo-7-ethyl-benzo- furan there was obtained 2-chloroacetyl-5-bromo-7-ethyl benzo- 2-Chloroacetyl-5-bromo-7-ethyl-benzofuran was reduced in a mariner analogous to that described in the third, paragraph of Example 2A to give 2-[(2-chloro-l-hydroxy^ethy^-5-bromo-7- ethyl-benzofuran as a yellow oil. ' ' B) The process: ■ · Example 6 A) The preparation of the starting; materials: A solution of 20g of potassium hydroxide in 2 Oral of ethanol is added over a period of 0.2 hour at room temperature to a stirred solution of .56.8g (C.JJmol) . of.5-chloro-5-aietlyl-salicyladehyd.e in -33Cml of ethanol. 26795/2 28ml (0.34-mol) of chloro-acetone are added- dropwise to the resulting mixture over a period of 0.5 hour, then the mixture is stirred overnight at room temperature. The bulk of the ethanol is subsequently evaporated off under reduced pressure, water is added to the residue and the aqueous mixture is extracted twice with methylene chloride. The combined extracts are washed -with water and with brine, dried over anhydrous sodium sulphate and evaporated. The residual solid is crystallized from ethanol to yield ' 3 .7g of 2-acetyl-5-chloro-7-raethyl-bensofuran of melting point 1130~115°C. 55.5s (O.15210I) of trimethyl phenyl ammonium perbromide are added in a single' portion at room · temperature to a stirred solution of 31.3g (0.15 mol) of 2-acetyl-5-chloro-7-S!ethyl-benzofurari in 300ml of dry tetrahydro-furan. The resulting mixture is stirred for 2 hours (during which time trimethyl pheny ammonium bromide precipitates out), then rjoured into a large excess of water and extracted twice -with, ether The combined extracts are washed successively with · aqueous sodium bicarbonate solution", "water and brine, dried over., anhydrous sodium sulphate and evaporated. The crystalline residue is recrys.tallized twice from ethanol to yield 26.3g of 2-bromoacetyl-5-chloro-7- -methyl-bens0furan of melting point 108°-111°C. 2.2g of sodium borohydride are added portionwise over a period of 0„ diour at room temperature to -a stirred solution of 26. g (0.09mol)- of 2-bromoacetyl- -5-chloro-7-itiethyl-ben7Jofuran in lSCml' of ethanol end the resulting mixture is stirred at room temperature for 5 hours. Sthanol is then evaporated off under reduced pressure and the residue is diluted with water and extracted twice with ether. The combined extracts are washed with water and with brine, dried over anhydrous sodium sulphate and evaporated to yield 26g of crude 2-[(2-bromo-l-hydroxy)-ethyll -5-chloro-7-methyl--benzofuran.

B) The process: 26g of crude 2-[(2-bromo-l-hydroxy)-ethyl3 -5-chloro--7-methyl-benzofuran and 32.3s .(0.54-mol) of i_opropyl amine in lCOml of isop opanoljare heated at reflux for 24 hours. The resulting mixture is. cooled and solvent and excess isopropyl amine are evaporated off. The residual gum is partitioned between ether and dilute hydrochloric acid. The aqueous acidic solution is separated, washed with ether, made basic dilute aqueous sodium hydroxide solution and extracted twice wit ether. The combined extracts are washed with water and with brine, dried over anhydrous sodium sulphate and evaporated. The residual yellow solid is crystallized from ethyl acetate to yield 6.4g of 2-j(2-is propylamino-l-hydroxy^-eth l3 -5-chloro-7-methyl--benzofuran of melting point 110°-112°C. The corresponding hydrochloride melts at 175°-177°C [after recrystallization from ethano-l/Cethyl acetate)].

The following Example illustrates the manner in which he novel derivatives provided by the invention may be made up. into pharmaceutical preparations: .

Example η g .of 2-(2-Isopropylamino-l-hydroxy^-ethyl|-5-niethyl-7-bromo-benzofuran hydrochloride were mixed with. 10 g of lactose.. The mixture was granulated using 0.5 g of 10?£ aqueous gelatin and the granulate was mixed with 2.5 g of maize starch. 0.25 g of stearic' acid were added. and the mixture was compressed according to known methods to give tablets each' containing.100 mg of active material.. ' ' -l6b~

Claims (4)

1. Having now particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we:*declare that what we claim is: 1. Process for the manufacture of benzofuran derivatives of the general formula wherein sents 5- or 7- (chloro or bromo) or 5>'7-di (chloro' or bromo) substitution and represents mono-, di- or tri (lower alkyl) substitution according to the availability of position or positions, and of acid addition salts thereof, characterized in that a halohydrin of the general formula wherein and have the above meaning and X is chlorine or bromine, is reacted with an amine of the general formula -NH2 (IV) in the presence of an acid-binding agent, or in that an epoxide of the general formula .,- wherein R and R^ have the above meaning, is reacted with an amine of the above formula IV, and that, if desiredJ the reaction product is converted into an acid addition salt.

2. Process as claimed in Claim 1, characterized in that a starting material of formula II or III is used, wherein R^- represents bromo substitution.

3. Process as claimed in Claim 1 or 2, characterized in that a starting material of formula II or III is used, wherein R^ represents mono- or dimethyl or mono- or diethyl substitution.

4. Process as claimed in any one of Claims 1 - 3» characterized in that an amine . starting material of formula IV is used, wherein R represents the isopropyl group. of formula I in Claim ,1 5· Process for the manufacture of berizofuran derivatives/ as hereinbefore particularly described,, especially with reference to the foregoin Examples 1 - 5» 6. Process for the manufacture of preparations having adrenergic blocking activity, characterized in that a benzo-furan derivative wherein R represents a lower alkyl group, R1 represents 5- or 7- (chloro or bromo) or 5»7-di (chloro or bromo) substitution and represents mono-, di- or tri (lower alkyl) substitution according to the availability of position or positions, or a pharmaceutically acceptable acid addition salt thereof, is mixed, as active substance, with nontoxic, inert, therapeu-tically compatible solid or liquid carriers and/or excipients commonly used in such preparations. 7. Compositions having adrenergic blocking properties, containing a benzofuran derivative of the general formula wherein. R represents a lower alkyl group, R-*- represents 5- or 7- (chloro or bromo) or 5>7-di (chloro or bromo) substitution and R2 represents mono-, di- or tri (lower1 alkyl) substitution according to the availability of position or positions,. or a pharmaceutically acceptable acid addition salt thereof, arid a carrier. 8. Benzofuran derivatives of the general formula wherein R represents a. lower . alky 1 group, R represents 5- or 7-(chloro or bromo) or 5 , 7-di (chloro or bromo) substitution and represents mono-,di- or tri (lower alkyl) substitution according to the availability of position or positions, and acid addition salts thereof, whenever prepared by the .process as claimed in any one Of Claims 1 - 5 , or by an obvious chemical equivalent thereof. 9. 2j^≥-Isopropylamino-l-hydrox3)-ethy^-5-bromo-6 , 7- dimethyl-benzofuran and acid addition salts thereof,whenever prepared according to the process claimed in any one of Claims ; 1 - 5 , or by an obvious chemical equivalent thereof. •'J ^ 10. 2-^-Isopropylamino-l-hydroxy>-ethyl7-5-bromo-7- methyl-benzofuran and acid addition salts thereof, whenever ! prepared according to the process claimed in any one of Claims i 1 - 5 > or by an obvious chemical equivalent thereof. prepared according to the process claimed in any one of Claims 1 - 5» or by an obvious chemical equivalent thereof. -3^ 12. 2-&2-IsopropylaminOrl-hydroxy)-ethyl -4-methyl-5,7-- 1 dibromo-benzofuran and acid addition salts thereof, whenever : prepared according to the process claimed in any one of Claims 1 - 5, or by an obvious chemical equivalent thereof. 13. 2-2f5-Isopropylamino-l--hydroxy)-ethy3^-5-bromo-7-ethyl- benzofuran and acid addition salts thereof, whenever prepared according to the process claimed in any one of Claims 1 - 5, or by an obvious chemical equivalent thereof. . n 14 -1-4), Benzofuran derivatives of. the general formula wherein R represents a lower alkyl group, R1 represents 5- or 7-(chloro or bromo) or 5,7-di (chloro or bromo) 5 ·' . substitution and R^ represents mono-, di- or tri (lower alkyl) substitution according to the availability of position or positions, and acid addition salts thereof. 15 4-7. 2-^^-Isopropylamino-l-hydroxy-ethy^-5-bromo-6,7-10 dimethyl-benzofuran and acid addition salts thereof. 1618* 2-2f2-Isopropylamino-l-hydroxy)-ethyl^-5-bromo-7- methyl-benzofuran and acid addition salts thereof. 171$-, 2-^2-Isopropylamino-l-hydroxy)-ethyJ^-5-methyl-7- bromo-benzofuran -and acid addition salts thereof. 15 182Q-. 2-^2-Isopropylamino-l-hydroxy>-ethyJ¾-4-methyl-5,7- , dibromo-benzofuran and acid, addition salts thereof. _¾ v 19-Hfc> 2-^"2-Isopropylamino-l-hydroxy)-ethy^-5-bromo-7-ethyl- benzofuran and acid addition salts thereof. '■■