US3200132A

US3200132A - Aminomethyl-benzofurans

Info

Publication number: US3200132A
Application number: US215530A
Authority: US
Inventors: Werner Lincoln Harvey
Original assignee: Ciba Geigy Corp
Current assignee: BASF Corp; Novartis Corp
Priority date: 1962-08-08
Filing date: 1962-08-08
Publication date: 1965-08-10
Anticipated expiration: 1982-08-10
Also published as: BE623403A

Description

United States Patent 3,200,132. AMINOMETHYL-BENZOFURANS Lincoln Harvey Werner, Summit, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 8, 1962, Ser. No. 215,530 11 Claims. (Cl. 260-6461) This is. a continuation-impart of application Serial No. 144,061, tiled October 10, 1961, and now abandoned. The present invention relates to 2,3-dihydro-henzofuran derivatives. More particularly, it concerns Z-aminomethyl-2,3-dihy drobenzofurans of the formula:

R1- H2-NH- s 2n R2 in which R represents a 2-(2,3-dihydro-henzofuranyl) radical, n stands for a whole number from one to seven,

and R represents a cycle-aliphatic, a carbocyclic aryl or a heterocyclic aryl radical, or salts of such compounds, as well as process for the preparation thereof.

A 2-(2,-3-dihydro-benzofuranyl) group R is particularly a group of the formula:

to any of the four positions available for substitution in' a 1, 2-p'henylene radical. Substituents attached to the 1,2- phenylene radical are, for example, an aliphatic hydrocarbon radical, such as lower alkyl, e.g. methyl, ethyl,

n-propyl, isopr-opyl, nabu-tyl and the like, hydroxyl, etheritied hydroxyl, particularly lower alkoxy, e.g.-methoxy, ethoxy, npropyl=oxy, isopropyloxy, n-butyloxy and the like, as well as lower al-kenyloxy, e.g. allyloxy, Z-methylallyloxy and the like, lower ialkylene-dioxy, e.-g. methylened-ioxy, L l-ethylenedioxy and the like, cycloalkyloxy, in. .which cycloalkyl has from five to eight, preferably from five to six, carbon atoms, e.g. cy-clopentyloxy, cyclohexyloxy and the like, carhocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g. phenoxy and the like,

carbccyclic iaryl-aliphatic et'herified hydroxyl, such as monocyclic carbocyclic aryl-lower alk-oxy, for example, phenyl-lower alkoxy, e.g. .benzyloxy, l-phenylethoxy, 2- phenyleth-oxy and the like, esterilied hydroxyl, especially halogeno (representing hydroxyl esterified by a hydrohalic acid), e.g. fluoro, chloro, bromo and the like, trilluoromethyl, mercapto, etherified mercapto, such as lower alkyl-mercapto, e.g. methylmercapto, ethyl-mercapto and the like, nitro, amino, such as N,=N-d-i-lower alkyl-am1no, e.g. N,N-.d-imethylarnino, N-ethyl-tN-rnethylamino, N, N-diethylain'ino and the like, or N-acylamino,

such as N-lower alkanoyl-amino, e.g. N-acetylam-ino, N- propionylamino and the like, or N-carbocyclic aroylamino, e.g. 'N-benzoylanrino and the like, acyl, such as, for example, lower alkanoyl, e.g. acetyl, puopionyl, butyryl, isobutyryl, piualoyl and the like, as well as car- =bocyclic aroyl, such as monocyclic carbocyclic aroyl, e.g. benzoyl and the like, carbocyclic aryl-lower alkanoyl, suhas nronocyclic car bocyclic aryl-lower alkauoyl, for example, phenyl-lower alkanoyl, e.g. phenylacety-l and the like, or any other analogous, suitable substituent.

Substituted 1,2 pheny1ene groups are, for example, aliphatic substituted-1, 2phenylene, such as lower alkyl-1,2-

ice

phenylene, e.-g. methyl-1,2-phenylene (such as 3-methyl- 1,2-phenylene, 4-methy1 1;2-phenylene, 4,5-dimethyl l,2- phenylene and the like), ethyl-.l,2-phenylene (such as 4- ethy1-l;2-phenylene and the like, n-propyl-1,2-phenylene (such as 4-n-propyl-1,2-phenylene and the like), isopropyl-LZ-phenylene (such as 3-isopropyl-1,2-phenylene and the like), or any other analogous lower alkyl-l,2- phenylene radical, hydroxy-l,2phenylene (such as 3-hydroxy 1,2-phenylene, 4-hydroxy-il,2-phenylene and the like), etherified hydroxy-lQ-phenylene (such as 3-meth- 0xy-'1,Q-.phenylene, 4-methoxyl,2-phenylene, 3,4-dimethoxy-'1,'2-phenylene and the like), ethoxyalfl-phenylene (such as 3-ethoxy-1,Z-phenylene, 4-ethoxy-1,2-phenylene,

3,6-diethoxy-l,Z-phenylene and the like), n-p-ropyloxyl,='2-pheny1ene (such as 4-n-propyloxy-l,2-pheny1ene and the like), isopropyloxy-l,Z-phenylene (such as 3-isopropyloxydQ-phenylene and the like), n-butyloxy-1,2 phenylene (such as 4-n-butyloxyd,2-phenylene and the like), or any other analogous lower -a lkoxyal,2-phenylene radical, lower alkenyl oxy-il,Q-phenylene, e.g. allyloxy-l,2- phenylene (such as 3-iallyloxyl, 2-phenylene, 4-allyl-oxy- 1,2-phenylene and the like), or any other analogous lower alkenyloxy-1,2-phenylene radical, lower alkylenedioxy- 1,2-p'henylene e.g. rnethylenedioxy-1,2-phenylene (such as 3,4-rnethylenedioxy 1,Zaphenylene and the like), or any other analogous lower alkylenedioxy-1,2 phenylene radical, cycloa1-kyloxy-1,-2-phenylene, in which cycloalkyl has from three to eight, preferably from five to six, carbon atoms, e.g. cyclopentyloxy-1,2ephenylene (such as 3-cyclopentyl-oxyl-l,2-phenylene and the like), cyolohexyloxy-1,2- phenylene (such as 4-cyclohexyloxy-1,2-phenylene and the like) or any other analogous cycloalkyloxy-l,2-phenylene radical, monocyclic carhocyclic aryloxy-1,2-phenylene, e.g. phenyloxy-'1,2-phenylene (such as S-phenyloxy- 1,-2-phenylene and the like) or any other analogous monocyclic carbocyclic aryloxy l,2-phenylene radical, monocyclic carhocycl'ic aryl-lo-wer alkoxy-l,2-phenylene, such as phenyl-lower alkoxy-l,2-phenylene, e.g. benzyloxy-1,2-

'phenylene (such as 3-benzyloxy-l,Q-phenylene, 4-benzyloxy l, 2-phenylene and the like), 2-phenylethoxy-1,2- phenylene [such as 3-(2-phenylethoxy)-l,2-phenylene and the like] or any other analogous mon ocyclic carbocyclic .aryl-lower alkoxy-1,2-phcnylene radical, esterified hydroxy-1,2-phenylene, particularly halogeno-xl,2-phenylene, e.g. fluoro1,2-phenylene (such as 3- fluoro-1,'2-p henylene, 4-fluo-ro- 1,2-phenylene and the like), chloro-LQ- phenylene (such as 3-chlor0-l,Z-phenylene, 4-chlo-ro l,2- phenylene, 4,5dichloro-f1,Z- henylene, 3,4,5,6tetrachloro-1,2-phenylene and the like), ibromo-l,2-phenylene (such as 4-bromo-rl,2-phenylene, 3,6-dibronro-1,2-phenylone and the like), or any other analogous halogeno-l,2- phenylene or esteritied hydroxy-LZ-phenylene radical, trifluoromethyl-1,2-pheny1ene (such as 4-trifiuoromethyl- 1,2-phenylene and the like), mercapto-LQ-phenylene (such as 4-mercapto-L'Z phenyIene and the like), etherified meucapto-1,2-phenylene, such as lower .alkylrnercaptm 1,2-phenylene, e.g. methylmercapto-l,2-phenylene (such as 4-rnethylmercapto-1,2-phenylene and the like), ethylmercapt0-1,2-phenylene (such as 3-ethylrnercapto-L2- phe-nylene and the like), or any other analogous lower alkyhnercapito-1, 2-phenylene radical, nitro-l,2-phenylene (such as 3-nitro-1,2-phenylene, 4nitro-l,2-phenylene and the like), 'N;N- di-l-ower alkyl amino-1,2-phenylene, e.g. N,Ndimethylanrino41,2-phenylene (such as 3-'N,-N- d-imethylamino-l,2-phenylene, 4-N;N-dimethy l-amirro-1,2- phenylene and the like), N-ethyl-N-methyl-amino-l,2- phenylene (such as 4-N-ethyl-N-rnethylamino-l,2-phenylene and the like), N,N-diet-hylamino-l,Z-phenylene radical, N-acyhamino-l, 2-phenylene, such as N-lower alkanoyl-amino-1,-2-phenylene, e.g. N-acetylamino-1,2-

phenylene (such as 4-N-acetyl-amino-l,2-phenylene and the like), N-piva'loylaminod,Z-phenylene (such as 4-N- pivaloylamino l,2-phenylene and the like), as well as N- benzoylarnino-l,Z-phenylene (such as 4- N benzoylamino- 1,2-phenylene and the like), or any other analogous N- acyl-amino-1, 2-phenylene radical, or aCyI-LZ-phenylene, such as lower alkanoyl-lfi-phenylene, e.g. ace'tyl-1,2- phenylene (such as 3-acetyll,2-phenylene, 4-acetyl-l,2-

'phenylene and the like), propionyl-1,2-pl1enyl-ene-l,2-

p'henylene (such as 3-pr-opionyl-1,Z-phenylene and the like), butyryI-LZ-phenyIene (such as 4.butyryl-1,2-phenylene and the like), pivaloyl-1,2-phenylene (such as 3- pivaloyl LQ-phenylene and the like) or any other analog-ous lower alkanoyl-1,2-phenylene radical, monocyclic carbocyclic anoyl-1,2-phenylene, e.g. benzoyLLZ-phenylone (such as 3abenzoyll,Z-phenylene, 4-benzoyll,2- phenylene and the like) or any other analogous monocyclic canbocyclic 'aroyl-1,2-phenylene radical, monocyclic carbocycli-c aryl-lower alkanbyl-LZ-phenylene, such as phenyl-lower alkanoyl-LZ-phenylene, 6.g. phenylacetyl- 1,2-phenylen-e (such as 3-p-henylacetyl-1,2-phenylene and the like) or any other analogous monocyclic aryl-lower .alkanoyl-lgZ-phenylene radical, or any equivalent substituted 1,2-phenylene radical.

The alkylene radical represented by C,,H in the above formula, in which the letter it may stand for a whole number from one to seven, has preferably from one to four carbon atoms (the letter 11', therefore, stands preferably for-a whole number from one to tour), which carbon atoms may be arranged in a straight or a branched carbon chain. Such alkylene radicals may be represented by methylene, 1,1-cthylene, 1,2-ethylene, 1methyl-1,2-etl1- ylene, 2-methyl-1,2-ethylene, 1,3-propylene, l,4-butylene and the like, as well as 1,4-pentylene, 1,5-pentylene, 1,6-

hexylene, 1,7-heptylene and the like.

A cycloaliphatic radical R is preferably saturated and represents, therefore, primarily cycloalkyl. However, it

may also contain one or more than one double bond, de-

pending on the number of ring carbon atoms. A cycloalkyl group may have from five to eight, preferably from five to six, ring carbon atoms and is, therefore, primarily cyclopentyl or 'cyclohexyl, as well as cycloheptyl or cyclo- 4 isobutyl and the like, lower alkoxy, egxmethoxy, ethoxy, n-propyloxy, isopropyloxy,n-butyloxy and the like, halogeno, e.g.,fluoro, chloro, bromo and the like, or any other suitable substituent.

Salts of the new compounds of this invention are part1- cularly acid addition salts, such as the non-toxic, pharmaceutically acceptable acid addition salts, forexample, those with inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, with organic carboxylic acids, e.g. formic, acetic, propionic, glycolic,

malonic, maleic, hydroxymaleic, furamic, malic, tartaric, citric, ascorbic, benzoic, ,salicyclic, 4 amino'salicylic,

' '2-phenyloxybenzoic, 2-aceto'xybenz'oic acid and the like,

octyl. A cycloaliphatic radical having one or more than one double bond is particularly acycloalkenyl group, which has from five to eight, preferably from five to six, carbon atoms; cycloalkenyl groups are, for example, l-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, l-cyclohexenyl, 2-cycl0hexenyl, 3-cyclohexenyl and the like, as well as 3.-cycloheptenyl, 2-cyclo-octenyl and the like. The cycloaliphatic radicals are preferably unsubstituted, but

may contain substituents, such as, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, or functional groups, such as halogeno, e.g. chloro, bromo and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, or any other suitable functional group.

A carbocyclic aryl radical R is more particularly a monocyclic carbocyclic aryl radical, e.g. phenyl or substituted phenyl, or a bicyclic carbocyclic aryl radical, e.g.

1-naphthyl, Z-naphthyl or substituted l-naphthyl or substituted 2-naphthyl. One or more than one of the same or of different substituents may be attached to any of the positions available for substitution in a phenyl or naphthyl radical; such substituents are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy'and the like, halogeno,

eg. fluoro, chloro, bromo and the like, trifiuoromethyl, 'nitro, amino, such as N,N-di-lower alkyl-amino and the like, or any other suitable substituent.

A heterocyclic aryl radical R 'is preferably a monocyclic heterocyclic aryl radical, such as pyridyl, e.g. 2-pyridyl, 3-pyridyl or 4 pyridyl, thienyl, e.g. Z-thienyl and the like, furyl, e.g. 2-furyl and the like; these groups may contain additional substituents, such as, for example, low- .er alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,

or with organic sulfonic acids,,e.g..methane sulfonic,

ethane sulfonic, Z-hydroxyethane sulfonic, ethane 1,2-disulfonic' acid, benzene sulfonic, p-toluene sulfonic, naphthalene 2-sulfonic' acid and the like;- Other acid addition salts may be useful as intermediates, for example, in the purification of the free compounds or .in the manufacture of other salts, as well as for identification and characterization purposes. Salts which are primarilyused for, identification purposes are particularly those Wlih aCIdIC orin which R, is cycloalkyl having from five to eight carbon atoms and stands primarily for cyclopentyl or cyclohexyl, or phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl,

(halogeno)-phenyl or pyridyl, the group R stands for hydrogen, lower alkyl, lower alkoxy, halogeno, trifluoromethyl, nitro, N,N-di-lower alkyl-a'mino or lower alkanoyl, and the letter n represents a whole number from one to four, andthe acid addition'salts of such compounds.

The new compounds of this invention may be used in the form of compositions for oral or: parenteral use, which contain the new compounds or the salts thereof in admixture with an organic or inorganic, solid or liquid carrier. For making up such compositions there are employed substances. which do not react with the new compounds, such as water, gelatin, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propylene glycol, polyalkylene glycols, petroleum jelly or any other known carrier used for such preparations. The latter may be in solid form, for example, as tablets, dragees, capsules and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like, and, if desired, may contain auxiliary substances, such as preserving, stabilizing,

wetting, emulsifying, coloring,- flavoring agents and the i like, salts for varying-the osmotic pressure, buffers, etc.

They may also contain, in combinatiomother useful substances.

The compounds of this invention may be prepared according to methods known perse. Iprefer to manufacture these compounds by treating an amine of the formula R -(C,,H2n)NI-I' in which R and the letter 12 have the previously-given meaning, with a compound of the formula R CH X, in which R has the previously-given meaning, and X represents a reactive 'esterified' hydroxyl group, and, if desired, converting a resulting salt into a free compound or into another salt, and/or, if

desired, converting a free'compound into; a salt thereof, and/or, if desired, introducing a substituia'nt intQ the e bocyclic aryl portion of the 2,3-dihydro-benzofurane nucleus, and/ or, if desired, converting a substituent attached to the carbocyclic aryl portion of the 2,3-dihydro-benzofuran nucleus into another substituent.

The reactive esterified hydroxyl group X in a compound of the formula R -CH -X is particularly a hydroXyl group esterified with a strong inorganic acid, such as a mineral acid, particularly a hydrohalic acid, e.g. hydrochloric, hydrobromic, hydriodic acid and the like, as well as sulfuric acid and the like, or a strong organic acid, particularly a strong organic sulfonic acid, such as a monocyclic carbocyclic aryl sulfonic acid, e.g. p-toluene sulfonic acid and the like, or a lower alkane sulfonic acid, e.g. methane sulfonic acid, ethane sulfonic acid and the like. The group X in the above formula is above all represented by halogeno having an atomic weight greater than 19, such as chloro, bromo or iodo.

The reaction is preferably carried out by treating the amine with the reactive ester compound in such a way that an excess of the amine is always present. Alcohols, such as lower alkanols, e.g. methanol, ethanol and the like, or any other suitable direct diluent may serve as sol- .vents. If necessary, an alkaline reagent, such as an alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate and the like, or an organic base, e.g. pyridine and the like, may be used to neutralize the generated acid.

The reaction is preferably performed at an'elevated temperature, if necessary, in a closed vessel under pressure and/or in the atmosphere of an inert gas, e.g. nitrogen.

The starting materials used in the above reaction are known or may be prepared according to methods used for the preparation of the known compounds.

The compounds of this invention may also be prepared by reacting a compound of the formula R -CH -NH in which R has the previously-given meaning, with a compound of the formula R -(C H )X, in which R X and the letter n have the previously-given. meaning, if desired, carrying out the optional steps.

This reaction is carried out according to the previouslydescribed procedure; the starting materials are known or may be prepared according to procedures used for the known compounds.

The compounds of this invention may also be obtained by converting in a compound of the formula in which R R and the letter n have the previouslygiven meaning, the carbonyl group into methylene, and, if desired, carrying out the optional steps.

Conversion of the carbonyl portion of the amide group into methylene is carried out according to known methods, particularly by treatment with a reducing reagent capable of converting the carbonyl portion of the amide grouping into methylene. Such reducing reagents are especially alkali metal aluminum hydrides or alkaline earth metal aluminum hydrides, particularly lithium aluminum hydride as well as sodium aluminum hydride and the like; if necessary, these reagents may be used in the presence of an activator, for example, aluminum chloride and the like. The reaction is carried out in the presence of a suitable solvent, for example, an ether, e.g. diethylether, tetrahydrofuran and the like, and, if necessary, at an elevated temperature, for example, at the refluxing temperature of the solvent. Conversion of the carbonyl group into methylene may also be achieved by electrolytically reducing the amide on a suitable cathode, such as mercury, lead, nickel cathode and the like, using a proper anode and suitable catholyte and anolyte media. Conversion of the carbonyl portion in an amide group into methylene may also be carried out by treatment with hydrogen in the presence of asuitable catalyst, e.g. certain copper catalysts and the like.

The starting materials used in the above reaction may be prepared according to procedures generally used for the preparation of carboxylic acid amides, for example, by treatment of an acid halide, e.g., chloride, with an amine.

Compounds of this invention, particularly those of the formula C 1H2 2 R2, in which R R and the letter n have the previously-given meaning, or salts thereof, may also be obtained by converting in a compound having the formula in which R R and the letter n have the previously-given meaning, the carbonyl group into methylene, and, if desired, carrying out the optional steps.

The above reaction is carried out according to the previously-described methods, and the starting materials are prepared according to known procedures.

The compounds of the present invention may also be prepared by converting in a compound of the formula R CSNH(C H )R in which R R and the letter w have the previously-given meaning, the thiocarbonyl group into methylene, and, if desired, carrying out the optional steps.

The above conversion of a thiocarbonyl group into a methylene group may be carried out according to known methods, for example, by treating the thioamide compound with freshly prepared Raney nickel in a suitable, particularly in an alcoholic, solvent, e.g., methanol, ethanol and the like, or electrolytically reducing it according to the procedure outlined hereinabove for the reduction of the amides.

The starting materials may be prepared, for example, from the previously-described amides by treatment with liukitable reagents, e.g., phosphorus pentasulfide and the Another method for the preparation of compounds of this invention, particularly of compounds having the formula R -CH NHCH (C,, H )R in which R R and the letter n have the previously-given meaning, comprises converting in a compound having the formula (C 1Hg 2 -R2, in which R R and the letter 11 have the previously-given meaning, the thiocarbonyl group into methylene, and, if desired, carrying out the optional steps.

The above procedure is carried out as shown hereinbefore, and the starting material is prepared according to known methods.

Compounds of this invention, particularly those of the formula R1-CH2NH-CH2(C 1H2 2)-R2, in which R R and the letter 11 have the previously-given meaning, or salts thereof, may also be obtained by removing in a compound of the formula in which R and R and the letter n have the previouslygiven meaning, the Schiff base-type N C- double bond by reduction, and, if desired, carrying out the'optional steps.

The reduction of the Schiff base-type double bond may be carried out by using catalytically activated hydrogen or a di-light metal hydride as hydrogenating agents. Catalysts containing a metal of the eighth group of the periodic system may be used in the presence of hydrogen; for example, palladium, e.g., palladium on charcoal and the like, represents a suitable metal catalyst. The reduction is carried out by treating, for example, a lower alkanol, e.g., methanol, ethanol and the like, solution of the Schiif base with hydrogen, if desired, at an increased pressure, in the presence of the catalyst.

The preferred reduction reagents, however, are light metal hydrides, particularly the alkali metal borohydrides,

e.g., lithium borohydride, sodium borohydride and the like, as well as alkali metal aluminum hydrides, e.g., lithium aluminum hydride, sodium aluminum hydride and the like, alkaline earth metal aluminum hydrides, e.g., magnesium aluminum hydride and the like, or any other suitable light metal hydride. The reduction with these reagents is preferably carried in solution,,the solvents being chosen according to the reactivity of the reagent. For'example, an alcohol, such as a lower alkanol, e.g., methanol, ethanol, isopropanol and the like, if desired, aqueous mixtures thereof, and the like, may be used with an alkali metal borohydride; an ether, e.g., diethylether, tetrahydrofurane and the like, is used with an alkali metal aluminum hydride. If desired, the reaction may be promoted by the. addition of an activator, for example, of aluminum chloride and the like. The

reaction is performed at room temperature or preferably;

at an elevated temperature, for, example, at the boiling temperature of the solvent, and, if necessary, in the atmosphere of an inactive gas, e.g., nitrogen.

The Schifl base-type starting materials may be prepared according to methods known per se, for example, by reacting a 2-aminomethyl-2,3-dihydro-benzofuran with an aldehyde, if necessary, in the presence of a solvent, such as an alcohol, for example, a lower alkanol, e.g., methanol, ethanol and the like, and or under cooling at room temperature or at an elevated temperature.

The compounds of this invention may also be prepared by removing in a compound of the formula in which R R and the letter n have the previouslygiven meaning, the Schitf base-type C N- double bond by reduction, and, if desired, carrying out the optional steps.

bond is carried out as previously shownythe starting material is prepared according to known methods.

A resulting salt may be converted into the free base in the customary way,'for example,- by reaction with an alkaline reagent, such as a metal hydroxide, e.g.sodium hydroxide, potassium hydroxide and the like, a metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate. and the like, ammonia and the like, or with a suitablehydroxyl ion exchange preparation. v

A resulting salt may be converted into another salt, for example, by treating it with a metal, e.g. sodium, barium, silver and the like, salt of an acid in the presence of a suitable diluent, in which a resulting inorganic salt is insoluble, or with an anion exchange preparation.

A free base may be converted into an acid addition salt by reacting it or a solution thereof with the appropriate inorganic or organic acid, such as one of those outlined hereinbefore, or a, solution thereof, and isolating the desired salt.

A substituent may be introduced into the carbocyclic aryl portion of the 2,3-dihydro-benzofuran nucleus of a resulting compound. For example, upon nitration with a suitable nitrating reagent, a nitro group may be introduced. Furthermore, a resulting compound may be reacted with an organic carboxylic acid halide, e.g.chloride and the like, in the presence of 'a suitable reagent, such as aluminum chloride and the like, and an organic carboxylic acid acyl radical may be introduced.

Certain substituents attached to the carbocyclic aryl portion of the 2,3-dihydro-benzofuran nucleus may be converted into other substituents. For example, a nitro group may be reduced to an amino group according to known reduction methods, for example, by controlled treatment with hydrogen in the presence of a suitable cata lyst, e.g. palladium on charcoal and the like, and of an inert solvent, e.g. p-dioxane and the like. An amino group may be converted into a halogeno atom by diazotization, followed by treatment with a cuprous halide according to the Sandmeyer reaction. Or, a-lower alkoxy, e.g. methoxy and the like, group may be converted into a free hydroxyl group, for example, by acidic hydrolysis with The reductive removal of the Schiff base-type double thereon. Temperatures are given in degrees centigrade.

- Example 1.

A mixture of 4.9 g. of 2-bromomethyl-7-methoxy-2,3- dihydro-benzofuran and 6.8 g. of 2- cyclopentylethylamine in 15 ml. of ethanol is heated in a sealed tube for four hours. The solution is concentrated under reduced pressure, and the residue is treated with waterand extracted with diethyl ether. The organic solution is dried and evaporated; the residue is dissolved in ethyl acetate, anhydrous hydrogen chloride in ethyl acetate is added and the crystalline 2 (Z-cyclopentylethyl)-aminomethyl-7-methoxy-Z,3-dihydro-benzofuran hydrochloride of the formula:

is recrystallized from ethanol, M.P. 160-163", yield: 2.3 g.

The-starting material used in the above example is prepared as follows: A mixture of 124.1 g. of guaiacol, 140 g. of powdered potassium carbonate and 121.0 g. ofallyl bromide in 150 ml. of acetone isrefluxed while stirring for eight hours. After cooling, it is poured into 1000 ml. of Water. and the organic material ,is extracted with diethyl ether. The solvent iseVapOrated, and the residue is distilled under reduced pressure to yield 129.2 g. of 2 allyloxy-anisole, B.P. /7 mm. After heating for 45 minutes to 230-240 and redistilling it, this material yields 119.6 g.of 2-allyl-6-methoxy-phenol, B.P. l10ll5/9 mm. Acetylation of 26.8v g. of 3-allyl-2-hydroxy-anisole with 30.6 g. of acetic acid anhydridein 24 g. of .pyridine yields29 g. of 2-acetyloxy-3-allyl-anisole, B.P. l09lll/ 2.5 mm. 1

To a solution of 31 got 2-acetyloxy-3-allyl-anisole in ml. of carbon disulfide is added dropwise 24.0 g. of bromine. After one hour, the reaction mixture is concentrated under reduced pressureand the residue is triturated with hexane to yield 26.0 g. of 2-acetyloxy-3-(2,3-dibromo-propyl) -anis0le.

To a solution of 2-acetyloxy-3-(2,3-dibromo propyl)- anisole in 320 ml. of ethanol is added a solution ofsodium ethoxide in ethanol (prepared by dissolving 7.0 g. of sodium in 300 m1, of ethanol) dropwise while cooling. The reaction mixture is then refluxed for one hour, the solution is cooled, filtered and concentrated under reduced pressure. The residue is taken up into diethyl ether, the organic solutionis washed with water, dried and concentrated. The desired 2-bromomethyl-7-methoxy-2,3- dihydro-benzofuran'is purified by distilling the residue, B.P. l38/1.5 mm.; yield: 45.25 g. l

Example 2 A mixture of 4.9 g. of 2-bromomethyl-7-methoxy-2,3- dihydro-benzofuran and 4.9 g. of 2-phenylethylamine in 15 ml. of ethanol is reacted as shown in Example. 1; the resulting 7-methoxy-2- (2-phenylethyl -aminoethyl-2,3-dihydro-benzofuran of the formula:

is converted into its hydrochloride by adding an anhydrous solution of hydrogen chloride in ethyl acetate to the solution of the free base in ethyl acetate and diluting I it with diethyl ether; it is recrystallized repeatedly from acetone, M.P. 137-l41; yield: 2.3 g.

Example 3 CH2 OCH CH-CHz-NH-CHrCHz- 0011 4101 precipitates and is recrystallized from ethanol, M.P. 19'6- 197.

The starting material is prepared according to the procedure described by R. Adams et al., J. Am. Chem. Soc., vol. 41, p. 648 (1919).

Example 4 To a solution of 5.1 g. of 5-acetyl-2-bromomethyl-2,3- dihydro-benzofuran in 30 ml. of ethanol is added 4.5 g. of 2-cyclopentylethyl-amine. The reaction is carried out according to the method described in Example 3; the 5 acetyl 2-(2-cyclopentylethyl) -aminoethyl-2,3-dihydrohenzofuran hydrochloride of the formula:

CHr-C Hg Ego-CO is recrystallized from isopropanol, M.P. 227-229.

The starting material, which is prepared according to the method described by R. Adams et al., loc. cit. by starting with 4-hydroxy-benzophenone, has a boiling point of 170/0.05 mrn.

Example 5 A solution of 9.72 g. of 2-bromomethyl-7-methoxy-2,3- dihydro-benzofuran in 30 m1. of ethanol is reacted with 14.4 g. of 2-(3,4-dimethoxy-phenyl)-ethylamine according to the procedure described in Example 3; the desired 2 [2-(3,4-dirnethoxy-'pheny1)-ethyl]-aminoethyl-7-methoxy-2,3-dihydro-benzofuran hydrochloride of the formula:

melts at l89-191 after being recrystallized twice from ethanol.

Example 6 A solution of 5.1 g. of 5-acetyl-2-bromomethyl-2,3 dihydro-benzofuran and 4.8 g. of Z-phenylethylamine in 30 ml. of ethanol is reacted as described in Example 3 to .10 yield to 5 acetyI-Z-(Z-phenylethyl)-aminomethyl-2,3-dihydrobenzofuran hydrochloride of the formula:

0 which is recrystallized from isoprop-anol, M.P. 238-242".

HaC-C 0 Example 7 To a solution of 5.1 g. of '5-acetyl-2-bromomethyl-2,3- dihydro-benzofuran in 30 ml. of ethanol is added 7.2 g. of 2-(3,4-dimethoxy-phenyl)-ethylarnine, and the mixture is reacted and worked up according to the procedure described in Example 3 to yield the 5-acetyl-2-[2-(3,4-dimethoxy phenyl) ethyl] aminomethyl 2,3 dihydrobenzofuran hydrochloride of the formula:

CH2 OCH:

which melts at 172-175 after being recrystallized three times from isopropanol.

Other compounds, which may be prepared according to the above-described procedure using the appropriate starting materials are, for example,

2-cyclopentylrnethylaminomethyl-2,3- dihydrobenzofuran,

2-cyclohexylmethylaminomethyl-2,3 -dihydrobenzofuran,

2-(3-cyclohexylpropyl)-aminomethyl-2,3-dihydrobenzofuran,

2-benzylamin-omethyl-2,3-dihydro-benzofuran,

2-(4-chlorobenzyl)-aminomethyl-2,3-dihydrobenzofuran,

2-(3,4-dimethoxy-benzyl)-arninomethyl-2,3-dihydrobenzofuran,

2-'( l-phenylethyl -aminomethyl-2,3-dihydro-benzofuran,

2- 1-'(4-methyl-phenyl) ethyl] -aminomet-hyl-2,3-dihydrobenzofuran,

2- 2-pyridyl) -me thylarninomethyl-Z,3-dihydrobenzofuran,

5-acetyl-2- Z-cyclohexylethyl -amin omethyl2,3

dihydr-o-benzofuran,

6-chloro-2- 2-cyclopentylethyl) -amin omethyl-2,3-

dihydro-benzofuran,

2- (Z-cyclopentylethyl) aminomethyl-3-mcthyl-2,3-

dihydro-benzofuran and the like. What is claimed is: 1. A member selected from the group consisting of a compound of the formula in which R is a member selected from the group consisting of hydrogen and lower alkyl, Ph represents a member selected from the group consisting of 1,2-phenylene, lower alkyl-1,2-phenylene, hydroxy-1,2-phenylcne, lower alkoxy-1,2-phenylene, halogeno-1,2-phenylene, trifiuoromethyl 1,2 phenylene, mercapto 1,2 phenylene, lower alkyl-mercapto-l,2-phenylene, nitro-1,2-phenylene, N,N-di-lower alkyl-amino-1,2-phenylene, N-lower alkanoyl-amino-l,2-phenylene, and lower alkanoyl-1,2-phenylene, the letter It stands for a whole number from one to seven, and R stands for a member selected from the group consisting of cycloalkyl having from 5 to 8 ring carbon atoms, cycloalkenyl having from 5 to 8 ring carbon atoms, phenyl, (lower alkyl)-pheny1, (lower a1- koxy)-phenyl, (halogeno)-pl1enyl, (trifluoromethyD- phenyl, (nitro)-phenyl, (amino)-phenyl, pyn'dyl, thienyl and furyl, and an acid addition salt thereof.

2. A compound of the formula:

in which R is phenyl, the group R is lower alkoxy, and V the letter n is a whole number from one to four.

in which R is (lower alkoxy)-phenyl, the group R is lower alkoxy, and the letter 11' is a whole number from one to four.

4. A compound of the formula:

m ou-oui-Nu-(on uzn m' in which R stands for-cycloalkyl having from '5 to 8 ring carbon atoms, the group R is lower alkoxy, and the letter n is a whole number from one to four.

l 2 5. An acid addition salt of a eompound ofthe formula:

R3 o11oHr -NH -(ona1;n' -R,'

in which Rjstandsfor cycloalkyl having from 5 to 8 ring carbon atoms, the group R is lower alkoxy, and the letter n is a Whole number from one to four. t

6. 2 (2 cyclopentylethyl)-aminon1ethyl-7-methoxy- 2,3-dihydro-benzofuran;

7. An acid addition salt of 2- (2-cyclopentylethyl)- aminomethy1-7-met hoxy-2,3-dihydro-benzofuran. I

8. 7 methoxy-Z-v(Z-phenylethyl)-aminomethyl-2,3-di hydro-benzofuran'.

9. An acid addition salt of 7-rhethoxy-2-(2-phenylethyl)-aminomethyl-23-dihydro-benzofuran;

10. 2 [2-(3,4-dimethoXy-phenyl)rethyl]-arninomethyl- 2,3V-dihydro-benzofuran.

'11. An acid addition salt of 2-v[2-.(3,4-dimethoxyphenyl) -ethyl] -aminomethyl-Zfl-dihydro-benzofurau.

9 References Cited by the Examiner Fieser: Organic Chemistry, third edition (1956)., pages 46-7. 7

Harington (editor): Hypoten'sive Drugs (195 8) page 1 1. V

NICHOLAS S. RIZZO, Primary Examiner

Claims

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA