Anti-inflammatory substituted benzofuran

United States Patent 3917654

3-Phenyl benzofurans substituted at the 5, 6 or 7 position by a hydroxymethylketoalkyl group which are active anti-inflammatory agents.

05/368174

11/04/1975

06/08/1973

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Riku Laboratories, Inc. (Northridge, CA)

549/469

560/53, 549/466, 549/468

C07C45/71; C07D307/79; C07D307/80; C07D307/82; C07C45/00; C07D307/00; C07D5/40

260/346.2R

lundquist et al., Chem. Abstracts, (1972), Vol. 87, 47537..

Ford, John M.

Dentz, Bernard

Alexander, Sell, Steldt & DeLaHunt

What is claimed is

1. A compound of the formula ##SPC3##

2. A compound according to claim 1 wherein R¹ is hydrogen.

3. A compound according to claim 1 wherein R¹ is halogen and the group ##EQU8## is in the 7 position.

4. A compound according to claim 1 wherein R⁴ is hydrogen or methyl and R⁵ is hydrogen.

5. A compound according to claim 1 wherein Ar is halo-substituted phenyl.

6. A compound of the formula ##SPC4##

7. Hydroxymethyl 3-phenyl-7-benzofuranmethylketone according to claim 6.

8. 3-(4-Fluorophenyl)-7-benzofuranmethyl hydroxymethyl ketone according to claim 6.

9. Hydroxymethyl 2-[7-(3-phenyl)benzofuranyl]ethylketone according to claim 6.

This invention relates to 3-phenyl benzofurans substituted at the 5, 6 or 7 position by a hydroxymethylketoalkyl group which are active anti-inflammatory agents.

The invention also relates to methods of use of the compounds of the invention as anti-inflammatory and analgetic agents and to methods for the preparation of the compounds of the invention.

DETAILED DESCRIPTION

According to the present invention, there is provided a class of compounds of the formula ##SPC1##

Wherein R ¹ is hydrogen, or lower alkyl; R ² and R ³ are hydrogen or when taken together form a double bond, provided that when R ² and R ³ together form a double bond, R ¹ may be halogen and when R ¹ is halogen, the group ##EQU1## is in the 6 or 7 position; R ⁴ is hydrogen or methyl; R ⁵ is hydrogen or when taken together with R ⁴ forms a methylene group (=CH ₂ ); Ar is phenyl or substituted phenyl wherein the substituents are individually selected from lower alkyl, halogen, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower dialkylamino, lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl and hydroxy; each Y is individually selected from hydrogen, lower alkyl, lower alkoxy, halogen, dialkylamino and hydroxy; and p is zero, one or two.

Preferably R ¹ is hydrogen, although when R ¹ is halogen, the group ##EQU2## is preferably in the 7 position. Other preferred groups of the compounds of the invention are those in which R ² and R ³ together form a double bond, and in which R ⁴ is hydrogen or methyl and R ⁵ is hydrogen. When Ar is substituted, the substituents are preferably lower alkyl, lower alkoxy or halogen, most preferably halogen.

The compounds of the invention may be substituted on the benzo portion of the benzofuran ring in the 5, 6 or 7 positions. It is presently preferred that the group ##EQU3## is at the 6 or 7 position. The two Y groups (located at the remaining positions) can be the same or different. Preferably at least one Y group is hydrogen, most preferably both are hydrogen. When one Y group is other than hydrogen, it is preferably lower alkyl, lower alkoxy or hydroxy. Preferably, p is zero or one and most preferably p is zero.

When the term lower is used to refer to the alkyl portion of substituents herein, it refers to groups containing one to four carbon atoms, which may have straight or branched chains. When such alkyl or substituted alkyl groups are present, groups of one carbon atom are preferred.

When halogen substituents are present in compounds of the invention, halogen means fluorine, chlorine or bromine, and fluorine and chlorine are preferred.

In compounds of the invention wherein R ⁵ is hydrogen and R ⁴ is not hydrogen, the carbon atom to which R ⁴ is chemically bonded is an asymmetric carbon atom. In this case the compounds of the invention are generally present in the form of a racemic mixture. The resolution of such racemates can be carried out by a vast number of known methods. For example, some racemic mixtures can be precipitated as eutectics instead of mixed crystals and can thus be quickly separated and in such cases can sometimes be selectively precipitated. The more common method of chemical resolution is, however, greatly preferred. By this method diastereomers are formed from the racemic mixture by reaction with an optically active resolving agent. Thus, an optically active organic acid can be reacted with the --CH ₂ OH group. The difference in solubility between the diastereomers formed permits the selective crystallization of one form and regeneration of the optically-active acid from the mixture. There is, however, a third method of resolving which shows great promise. This method is one of the other forms of biochemical procedures using selective enzymatic reaction. Thus, the racemic alcohol compound can be subjected to as asymmetric oxidase which will by oxidation destroy one form, leaving the other form unchanged. Even more attractive is the use of a hydrolysase or esterase on a derivative of the racemic mixture to form preferentially one form of the alchol. Thus, esters of the alcohols can be subjected to an esterase which will selectively saponify one enantiomorph and leave the other unchanged.

When the free alcohol is resolved into (d) and (l) enantiomorphs, the anti-inflammatory activity is found to reside virtually completely in one isomer. The desired isomer of the free alcohol may be prepared by any one of the preceding described resolving methods, preferably working from the free alcohol as the starting material. Ester diastereomers of the alcohol may be formed with optically active acids.

The active form is generally the (d) form but absolute rotation and even the sign of rotation of the more active form can vary with substitution and compounds must be tested in biological assays to establish their relative activity.

In order to determine and assess the pharmacological activity of the compounds of the invention, testing in animals is carried out using various assays known to those skilled in the art, for example, the carrageenan or bradykinin induced rat foot edema test, the inhibition of ultraviolet-light-induced erythema test (guinea pig), the rat adjuvant arthritis assay, the Randall-Selitto assay, the phenylquinone writhing assay for analgetic activity and the like.

The compounds of this invention have a high degree of anti-inflammatory activity and are of value in the treatment of arthritic disorders and the like conditions which are known to respond to treatment by drugs with anti-inflammatory activity. In addition, the compounds of the invention have a useful degree of antipyretic and analgesic activity. For these purposes they are normally administered orally in tablets or capsules, the optimum dosage depending upon the particular compound being used and the type and severity of the condition being treated. Although the compounds are preferably administered orally, other known methods of administration are contemplated as well, e.g. dermatomucosally (for example dermally, rectally, and the like) and parenterally, for example by subcutaneous injection, intramuscular injection, intravenous injection and the like. Ocular administration is also included. Dosages ordinarily fall within the range of about 1 to 500 mg./kg. of body weight of the mammal to be treated although oral dosages are not usually above 100 mg./kg. and injection dosages are not usually above 50 mg./kg. Suitable forms for oral administration include liquids (such as four percent acacia suspensions), tablets (which may contain anhydrous lactose, microcrystalline cellulose, modified starch, calcium stearate and talc, as well as other conventional compounding agents together with the active anti-inflammatory agent) and capsules. Suitable carriers for topical application include creams, gels, tapes and the like. Liquid formulations, such as solutions or suspensions of the active ingredient in inert carriers, are contemplated for dosage by injection.

Compounds of the invention are active in one or more of the standard assays. Preferred compounds have a therapeutic ratio greater than 10.

The compounds of the invention are prepared by multistep synthetic sequences. The most convenient of these start with substituted phenols and form substituted benzofuran derivatives. The substituted benzofuran derivatives are then reacted to obtain the aliphatic side chain on the benzo ring. These skilled in the art will recognize that many variations of these sequences exist. The following discussion describes some of the useful processes for obtaining the compounds. The processes are represented graphically in the accompanying drawings.

Process A is represented by FIG. 1 wherein W is bromine, chlorine, iodine or methyl, Q is hydrogen or lower alkyl and Ar is as defined hereinabove.

In step (1) the reactants are generally known to the art, equimolar amounts of the reactants, or an excess of the phenol are reacted in the presence of a base, generally a weak inorganic base such as an alkali metal carbonate. A solvent is used, for example glyme, tetrahydrofuran, ethanol, pyridine and the like. An inert atmosphere may be used. The reaction is carried out at 50° to the reflux temperature. The compound of formula II is isolated by conventional methods such as extraction or elution chromatography.

In step (2) the compounds of formula II are cyclized by heating in polyphosphoric acid. The novel product compounds of formula III are easily separated and isolated by dilution of the reaction mixture with water and filtration or extraction.

Rearrangement of Ar from ring position 3 to 2 can occur if care is not taken in the cyclization step when Q = H. The structure of the product is verified by the ultraviolet absorption spectrum. 3-Phenyl derivatives have λ max about 228 and 254, ε about 25,000 and 13,000 respectively, while the 2-phenyl derivatives have λ about 300 with an ε of about 30,000.

Process B is represented by FIG. 2 wherein W, Ar and Alkyl are as defined hereinabove and steps (1) and (2) are essentially the same as steps (1) and (2) of Process A. The reaction of step (1) uses generally known reactants.

Process C is represented by FIG. 3 wherein Hal is chlorine, bromine or iodine and Ar is as defined hereinabove.

Step (1) reacts one mole of a known haloacetic acid, particularly chloracetic acid, with one mole of a known halophenol in the presence of two moles of strong base such as sodium hydroxide. The halophenoxyacetic acid product is readily isolated, or reacted further without isolation.

In step (2) the halophenoxyacetic acid is heated strongly with a pre-reacted phosphorus pentoxide-ethanol mixture to effect cyclization and dehydration to a coumaran-3-one. The product is readily isolated by conventional methods.

The coumaran-3-one is reacted in step (3) with an aryl Grignard reagent or ArLi using the methods and techniques well-known to the art. The product is readily isolated.

Process D is represented by FIG. 4 wherein W, Alkyl and Ar are as defined hereinabove.

The reactants of step (1) are known compounds, readily cyclized in base such as sodium ethoxide in ethanol to the corresponding benzofurans (VI). The compounds of formula VI are isolated by extraction.

In step (2) the hydrolysis of the ester to the acid is carried out under acidic or basic conditions. Alternatively, if W is methyl, hydrolysis is preferably preceded by bromination of the methyl group with N-bromosuccinimide under free-radical conditions such as are known to the art, followed by reaction with an alkali metal cyanide to give a cyanomethyl derivative.

Step (3), decarboxylation, is carried out by any of the well-known methods employed in the art, for example heating in quinoline in the presence of a copper catalyst.

Process E is represented by FIG. 5 wherein R ⁴ , Ar and Alkyl are as defined hereinabove and Y" must be hydrogen.

In step (1) a phenoxyacetophenone is formed as previously described in Process A, step (1).

In step (2) the cyclization is carried out as described in Process A, step (2) to give the novel intermediate VIII. Cyclization may occur at either of the positions Y", and when these positions are non-equivalent two different isomeric products are formed. These isomers are separated by conventional methods such as elution chromatography, vapor phase chromatography, fractional crystallization, and the like.

The intermediates of formula III, IV, V, VI and VII all contain the benzofuran nucleus with an aryl substituent at the 3 position. These intermediates are then used in further synthetic sequences wherein the objective is to provide compounds which also include the radical ##EQU4##

The compounds of formula VIII are compounds which may be hydrolyzed, under acidic or basic conditions, to provide other compounds substituted by the group ##EQU5## Furthermore, compounds of formula VIII may be transesterified using methods known to the art such as acidic or basic catalysis. The compounds of formula VIII may be converted to carboxylic acid halides by reaction with the usual reagents such as thionyl chloride and phosphorus pentachloride. The acyl halides can then be converted to products of the invention as described hereinafter.

The synthetic sequences whereby benzofuran intermediates are converted to intermediate carboxylic acids, are described further hereinbelow:

Process F is represented by FIG. 6 wherein Hal and Ar are as defined hereinabove.

Step (1) may be carried out by any of the well-known methods for preparing Grignard reagents; tetrahydrofuran is a preferred solvent.

Step (2) may be carried out by a standard Grignard reaction with formaldehyde, with subsequent acidification to the alcohol.

Step (3) requires displacement of the hydroxyl by a halide by any of the well-known methods of the art; for example reaction with a hydrohalogen acid, a phosphorus acid or thionyl halide, or conversion to the mesylate or tosylate. The reaction is preferably carried out in an inert solvent (for example benzene, toluene, xylene and the like) with thionyl chloride at any suitable temperature, but especially in benzene at reflux temperature until the reaction is substantially complete.

The displacement of the halide with a cyanide by any of the well-known methods of the art is the reaction of step (4). Suitable inorganic cyanides, for example sodium cyanide, potassium cyanide and the like, are reacted in an inert solvent, such as dimethylsulfoxide, dimethoxyfuran, acetone, aqueous alcohol and the like. As an example the reaction is carried out in an acetone-ethanol-water mixture with potassium cyanide at any suitable temperature, for example at the reflux temperature of the reaction mixture until the reaction is substantially complete.

In step (5) the reaction is hydrolysis of the nitrile by any of the variety of the methods well-known to the art, that is acidic, or basic hydrolysis, preferably basic hydrolysis with an alkali metal hydroxide in ethanol.

Process G is represented by FIG. 7 wherein Hal, Ar and Alkyl are as above.

In step (1) the Grignard reagent is reacted with an alpha keto ester, preferably ethyl pyruvate under any of the well-known Grignard condensation type reaction conditions.

In step (2) hydrolysis is accomplished by any means well-known to the art.

Step (3) is carried out by any dehydration procedure well-known to the art.

Step (4) is catalytic reduction by methods well-known to the art such as reduction over a catalyst, for example palladium, palladium on carbon, platinum, Raney nickel, platinum oxide and the like preferably under moderate hydrogen pressure (5 to 60 pounds) in an inert solvent such as lower alkanols, aromatic compounds, tetrahydrofuran, acetic acid, dioxane and the like at any suitable temperature, 0° C. to reflux temperature of the system, preferably at room temperature until the reaction is substantially complete.

Process H is represented by FIG. 8 wherein Hal, Alkyl and Ar are as defined hereinabove.

In step (1) the benzofuran is reacted with a halogenating agent. Presently preferred is N-bromosuccinimide. Free radical conditions which promote side chain halogenation are required, for example cobalt stearate and tertiary-butyl hydroperoxide may be used as a catalyst combination, and a strong source of visible light is commonly useful.

Step (2), displacement of the halide with a cyanide, is carried out as described in step (4), Process F.

Step (3), hydrolysis of the ester, is carried out by methods well-known to the art.

Step (4), simultaneous hydrolysis of the ester and the nitrile is carried out by vigorous hydrolysis with an alkali metal hydroxide in ethanol.

Step (5), selective decarboxylation, is carried out by heating in a guinoline-pyridine mixture until about one mole of carbon dioxide evolved.

Step (6 ), dicarboxylation, is carried out as described in step (3), Process D.

Step (7), hydrolysis of the nitrile, is carried out by the methods described for step (5), Process F.

Process I is represented by FIG. 9 wherein R ⁶ is methyl or ethyl and Alkyl and Ar are as defined hereinabove.

In step (1) the benzofuranacetic ester is converted to the reactive anionic intermediate by the action of a strong base such as sodamide, sodium hydride, lithium N,N-dialkylamide and the like. The anionic intermediate is used without isolation for step (2).

In step (2) alkylation is carried out by reaction with an alkyl halide such as methyl bromide, methyl iodide and ethyl bromide in an inert solvent such as benzene, diethyl ether, dimethyl sulfoxide and the like at any suitable temperature from -80° C. to reflux temperature until the reaction is substantially complete.

Process J is represented by FIG. 10 wherein Ar and R ⁶ are as defined hereinabove.

In step (1) the anionic intermediate is prepared as described in step (1), Process I.

In step (2), the alkylation is carried out as described in step (2), Process I.

The hydrolysis of step (3) is carried out as described in step (5), Process F.

Process K is represented by FIG. 11 wherein Hal, Ar, Alkyl and R ⁶ are so previously defined.

Step (1) is a Grignard reaction of a tert butyl alpha-haloacetate, alpha-halopropionate or alpha-halobutyrate by methods well-known to the art.

Step (2) is the hydrolysis of the ester under known acidic or basic conditions.

Process L is represented by FIG. 12 wherein X ¹ is ##EQU6## and R ¹ and Ar are as previously defined.

In this process reduction is carried out as in Process G, step (4) but requiring a longer time or more vigorous condition. An example is the use of a catalyst in a lower alkanol such as ethanol as the solvent.

Process M is represented by FIG. 13 wherein Hal and Ar are as previously defined hereinabove.

In step (1) the 2 position is halogenated with molecular halogen, preferably in an inert solvent. Chlorine and bromine are the preferred halogens.

Step (2) is side-chain halogenation effected as described in step (1), Process H.

Step (3) is carried out as described in step (4), Process F.

Step (4) is effected using the methods of step (5), Process F, preferably using acidic conditions.

Process N is represented by FIG. 14 wherein Hal, Ar and Alkyl are as previously defined hereinabove.

In step (1) the dialkyl malonate is treated with strong base such as sodium hydride, then reacted with the halomethyl-3-arylbenzofuran, preferably in ethanol.

In step (2) decarboxylation is readily effected by known methods, for example by heating the dry solid reactant to 150° to 200° C.

Process O is represented by FIG. 15 wherein Hal and Ar are as previously defined.

When this method is used R ¹ and Y may not be halogen, and Ar is not substituted by halogen.

In step (1) the benzofuran is reacted with cuprous cyanide in a solvent such as quinoline.

Step (2) is the reaction of the nitrile with methyl Grignard reagent.

In step (3) the methyl ketone is converted to a carboxylic acid by, for example, the Willgerodt reaction.

The intermediate acids are conveniently converted to the final compounds of the invention of formula I through the sequence shown in FIG. 16. wherein Z is ##SPC2##

Reaction (1) uses any of the well-known methods for the preparation of acid chlorides. Reaction with thionyl chloride has been found to be a very convenient route for obtaining the acid chloride.

Reaction (2) with diazomethane is a well-known reaction, discussed, for example in Organic Reactions, Volume 1, pages 38 ff. It has been found to proceed routinely in the class of compounds described by this invention. A non-reactive solvent such as diethyl ether is used. The diazoketone is a solid or liquid which may be isolated, but is generally not characterized. It is hydrolyzed as shown in step (3) under mildly acidic conditions in a suitable solvent, for example, dioxane. Suitable acids are organic or inorganic. Strong acids may be used, but they are generally dilute.

Compounds of the invention wherein Y is not hydrogen are prepared by the processes A through O described hereinabove by incorporating the substituents in the starting phenols, or by appropriate reaction of the intermediates as would be apparent to one skilled in the art. Other transformations of one substituent to another on the structure of formula I, constitute additional processes for the preparations of these compounds, i.e. the Ys are transformed to another set of Ys and/or Ar is converted to another Ar and/or R ¹ to another R ¹ by methods familiar to those skilled in the art. Examples include reactions as halogenation, alkylation of hydroxy groups and amines and oxidation of sulfides to sulfoxides.

The following examples are given for the purpose of further illustrating the procedures useful for obtaining the compounds of the invention but are not intended, in any way, to be limiting on the scope thereof. Thus, other processes and known and may be applied by those skilled in the art to obtain the compounds of this invention.

All melting points in the examples are uncorrected. The temperatures are given in degrees Centigrade and the pressures in millimeters of mercury.

EXAMPLE 1

Process A, step (1)

Phenacyl bromide (475 g., 2138 mole) is added to a mixture of 2-bromophenol (400 g., 2.3 mole) and potassium carbonate (470 g., 3.46 mole) in glyme (1600 ml) under a nitrogen atmosphere and the stirred mixture is heated to reflux temperature and maintained at reflux for eight hours. Some solid is present. The liquid portion is decanted, then evaporated to dryness. The residue after this evaporation is boiled in benzene and filtered.

The solid pot residue remaining after decanting is extracted with hot benzene several times, and these benzene extracts are combined with benzene filtrate. Hexane is added to the cooling benzene and a first crop collected. Partial evaporation gives a second crop. The white solid is alpha-(2-bromophenoxy)acetophenone, m.p. 113.5°-115°.

EXAMPLE 2

Process A, step (2)

Polyphosphoric acid (4200 g.) and alpha-(2-bromophenoxyacetophenone (596 g., 2.05 mole) are heated and stirred well at about 120° to 125° internal temperature for four hours. The reaction mixture is then poured into stirred ice and water (about 8 l. total volume) to give a suspension of white solid. The solid is collected and washed with water, cold dilute sodium hydroxide solution and water until the wash is neutral. The solid is recrystalled from hexane to give white crystals of 7-bromo-3-phenylbenzofuran, m.p. 72°-74°.

7-methyl-3-phenylbenzofuran is obtained by cyclizing the required acetophenone at about 80° for one to two hours. The optimum temperature and times vary with other substituents which may be present.

Additional intermediates of this type prepared by the general method of Process A illustrated by Example 1 and 2 include:

7-bromo-3-(4-fluorophenyl)benzofuran, m.p. 87°-91°

7-bromo-3-(3-chlorophenyl)benzofuran, m.p. 77°-79°

7-bromo-3-(4-bromophenyl)benzofuran, m.p. 70°-72°

7-bromo-3-(4-chlorophenyl)benzofuran, m.p. 116°-117°

7-bromo-2-methyl-3-phenylbenzofuran, m.p. 65°-72°

7-chloro-3-phenylbenzofuran, m.p. 75.5°-76.5°

7-bromo-3-(2-chlorophenyl)benzofuran, m.p. 76°-80°

7-bromo-5-methyl-3-phenylbenzofuran, m.p. 48°-50°

EXAMPLE 3

Process G, steps (1) and (2)

Dried magnesium turnings (46.2 g., 1.92 mole), dry tetrahydrofuran (200 ml.) methyl iodide (1 ml.) and a small portion of 7-bromo-3-phenylbenzofuran (total 465.7 g., 1.71 mole) are placed in a dry reactor. After the Grignard reaction is observed to be initiated the remaining benzofuran (diluted with 1 liter of tetrahydrofuran) is added gradually over 1.5 hours at a rate sufficient to maintain moderate reflux. Heating is continued an additional 15 minutes, then the mixture is allowed to cool.

Ethyl pyruvate (400 g., 3.45 mole) in dry tetrahydrofuran (3 1.) is cooled to -50° and the Grignard mixture is added slowly while maintaining the reaction temperature below -35°. The mixture is stirred well while allowing it to warm to room temperature over seven hours. The mixture is then heated to its reflux temperature and maintained at reflux for one hour. The mixture is evaporated in vacuo to concentrate it to about 1.5 liters. To this concentrate is added concentrated hydrochloric acid (200 ml.) and 1.5 liters of a mixture of ice and water. The organic phase is separated and the aqueous phase is extracted twice with dichloromethane. The organic phase is combined with these extracts and the solution is washed with saturated sodium chloride solution, then dried and concentrated by evaporation in vacuo to about one liter of an oil which is chiefly ethyl 2-hydroxy-2-[7-(3-phenyl)benzofuranyl]propionate.

This oil is dissolved in three liters of 95% ethanol and 200 ml. of water and the mixture is heated to its reflux temperature. A solution of potassium hydroxide (232 g.) in water (400 ml.) is added over about one hour. The mixture is maintained at its reflux temperature for 3.5 hours. The mixture is then concentrated to about one-half of its volume and the residue is poured into cold water (1.5 l.). The cloudy mixture is extracted with diethyl ether (700 ml. portions).

The aqueous phase is poured into excess dilute hydrochloric acid and the mixture is cooled and acidified with hydrochloric acid. The solid is collected by filtration and washed with several portions of hot water, then with petroleum ether. The white solid is 2-hydroxy-2-[7-(3-phenyl)benzofuranyl]propionic acid, m.p. 112.5°-117°.

Another intermediate compound prepared by the general method illustrated by Example 3 is 2-hydroxy-2-[7-(2-methyl-3-phenyl)benzofuranyl]propionic acid, m.p. 166°- 166.5°. In general the hydroxy acid may be used directly as obtained for the next step.

EXAMPLE 4

Process G, step (3)

Dry 2-hydroxy-2-[7-(3-phenyl)benzofuranyl]propionic acid (337 g., 1.19 mole) in toluene (3 l.) under a nitrogen atmosphere is treated with para-toluenesulfonic acid hydrate (70 g.) and hydroquinone (1 g.) while refluxing to azeotropically remove water in a Dean-Start trap. After refluxing for three hours the reaction mixture is cooled, diluted with hexane and cooled by an ice bath. The solid product is collected by filtration washed with petroleum ether, then aqueous ethanol to give 2-[7-(3-phenyl)benzofuranyl]acrylic acid, m.p. 195.5°-198.5°.

Additional intermediate compounds prepared by the general method illustrated in Example 4 include:

2-[7-(2-methyl-3-phenyl)benzofuranyl]acrylic acid, m.p. 180°-181°

2-{4-[3-(4-chlorophenyl)]benzofuranyl}acrylic acid, m.p. 175°-181°

2-{7-[3-(2-chlorophenyl)]benzofuranyl}acrylic acid, m.p. 189°-190°

2-{7-[3-(3-chlorophenyl)]benzofuranyl}acrylic acid, an oil

2-{7-[3-(4-fluorophenyl)]benzofuranyl}acrylic acid, m.p. 204°-206°

EXAMPLE 5

Process G, step (4)

2-[7-(3-Phenyl)benzofuranyl]acrylic acid (40 g., 0.15 mole) is dissolved in warm ethanol (750 ml.) and palladium on charcoal (3 g.) is added. The reduction is carried out using hydrogen gas at 40 psi. initial pressure. The mixture is filtered, then evaporated in vacuo to dryness. The residue is dissolved in benzene (225 ml.) diluted with hexane and cooled. The solid is collected by filtration and again recrystallized from a hexane benzene mixture. The white crystals obtained are 2-[7-(3-phenyl)benzofuranyl]propionic acid, m.p. 167.5°-168.5°.

______________________________________ Analysis: %C %H Calculated for C ₁₇ H ₁₄ O ₃ : 76.7 5.3 Found: 77.1 5.3 ______________________________________

Additional intermediate compounds prepared by the general method illustrated by Example 5 include:

2-[7-(2-methyl-3-phenyl)benzofuranyl]propionic acid, m.p. 146°-147°

2-{7-[3-(4-chlorophenyl)]benzofuranyl}propionic acid, m.p. 140°-141°

2-{7-[3-(3-chlorophenyl)]benzofuranyl}propionic acid, m.p. 150°-151°

2-{7-[3-(4-fluorophenyl]benzofuranyl}propionic acid, m.p. 169.5°-171.5°

2-{7-[3-(2-chlorophenyl)]benzofuranyl}propionic acid, m.p. 189°-190.5°

EXAMPLE 6

Process F, steps (1) and (2)

Dried magnesium turnings (12.2 g., 0.5 mole), dry tetrahydrofuran (50 ml.), methyl iodide (0.5 ml.) and a small sample of 7-bromo-3-(4-fluorophenyl)benzofuran (total 134 g., 0.46 mole) are placed in a dry reactor. After the Grignard reaction is observed to be initiated an additional 500 ml. of tetrahydrofuran is added, then the remaining benzofuran dissolved in tetrahydrofuran (500 ml.) is added over one hour at a rate sufficient to maintain a gentle reflux. The mixture is heated for an additional hour, then heating is stopped.

Paraformaldehyde (41.4 g., 1.38 mole) (dried over phosphorus pentoxide), is depolymerized at about 160° C. while passing the formaldehyde vapor into and over the stirred Grignard reaction mixture. The reaction is exothermic, causing a gentle reflux. Then reaction is complete, the mixture is concentrated to about one-third of its volume, then poured onto ice and water. Diethyl ether (50 ml.) is added, followed by slow addition of concentrated, cold 6N hydrochloric acid (250 ml.). The mixture is extracted with diethyl ether, the extracts are washed with water and saturated sodium chloride solution, dried and evaporated in vacuo to give an oil. The oil is dissolved in absolute ethanol (120 ml.) and concentrated hydrochloric acid (6 ml.) is added. The mixture is heated to reflux temperature and maintained at reflux for 2.5 hours. The mixture is evaporated in vacuo, then the residue is dissolved in diethyl ether, the solution is washed with water and saturated sodium chloride solution, dried and then concentrated to tan oil crude, 3-(4-fluorophenyl)-7-(hydroxymethyl)benzofuran. Pure product has m.p. 88°- 89°.

An additional intermediate compound of the invention prepared by the general method illustrated by Example 6 is:

7-hydroxymethyl-3-phenylbenzofuran, m.p. 76°-77° which can be obtained from either 7-bromo-3-phenylbenzofuran or 7-chloro-3-phenylbenzofuran. The crude intermediates can advantageously be used directly in the subsequent steps.

EXAMPLE 7

Process F, step (3)

3-(4-Fluorophenyl)-7-(hydroxymethyl)benzofuran (110 g., 0.45 mole) is dissolved in benzene (225 ml.) and added dropwise to refluxing thionyl chloride (110 ml.). Heating is continued until gas evolution is complete. Excess thionyl chloride and benzene are removed in vacuo, using additional benzene to aid in removing the thionyl chloride. The residue is a brown oil, 7-chloromethyl-3-(4-fluorophenyl)benzofuran.

EXAMPLE 8

Process F, step (4)

To a solution of 7-chloromethyl-3-(4-fluorophenyl)-benzofuran (130.3 g., 0.50 mole) in acetone (750 ml) and ethanol (500 ml) is added a solution of sodium cyanide (39.5 g., 0.50 mole) in water (150 ml). The mixture is heated to its reflux for five hours. The mixture is then evaporated in vacuo to concentrate it. The residue is dissolved in dichloromethane, then washed thoroughly with water, dried and concentrated by evaporation in vacuo. The oily residue is recrystallized twice from cyclohexane, then deposited on 70 g. of a silicate material used for elution chromatography and chromatographed on 400 g. of the silicate type column. Elution with hexane, benzenehexane (1:4), (1:1) and (3:2), followed by benzene gives the desired product, 7-cyanomethyl-3-(4-fluorophenyl)benzofuran, in the benzene fractions.

Additional intermediate compounds of the invention prepared according to the general method illustrated by Example 8 include:

7-cyanomethyl-3-phenylbenzofuran, m.p. 110°-111°

7-cyanomethyl-3-(4-chlorophenyl)benzofuran, m.p. 106°-120°

EXAMPLE 9

Process F, step (5)

Potassium hydroxide (85%, 49 g.), 7-cyanomethyl-3-(4-fluorophenyl)benzofuran (48.8 g., 0.194 mole) and 95% ethanol (500 ml.) are mixed and heated at reflux temperature overnight under a nitrogen atmosphere. The mixture is then concentrated by evaporation in vacuo, diluted with water and extracted with diethyl ether. The aqueous phase is filtered, then acidified by the slow addition of hydrochloric acid. The solid is collected by filtration and recrystallized from aqueous ethanol (65%) with treatment with decolorizing charcoal, giving yellow crystals. Another recrystallization from an ethanol-petroleum ether mixture (about 5:1) gives yellow crystals of 3-(4-fluorophenyl)-7-benzofuranacetic acid, m.p. 169°-170°.

______________________________________ Analysis: %C %H Calculated for C ₁₆ H ₁₁ FO ₃ : 71.1 4.1 Found: 71.0 3.8 ______________________________________

Additional intermediate compounds of the invention prepared by the general method illustrated by Example 9 include:

3-phenyl-7-benzofuranacetic acid, m.p. 143°-144°

3-phenyl-5-benzofuranacetic acid, m.p. 131.5°-132°

3-phenyl-7-(5-methoxybenzofuran)acetic acid, m.p. 161°-162°

3-phenyl-6-benzofuranacetic acid, m.p. 142°-144°

3-phenyl-7-(5-methylbenzofuran)acetic acid, m.p. 134°-135°

(2-methyl-3-phenylbenzofuran)-6-acetic acid, m.p. 197°-198°

3-(4-methoxyphenyl)-6-benzofuranacetic acid, m.p. 163°-164°

3-(4-methylphenyl)-6-benzofuranacetic acid, m.p. 148.5°-156°

3-(4-fluorophenyl)-6-benzofuranacetic acid, m.p. 151°-152°

3-(4-chlorophenyl)-7-benzofuranacetic acid, m.p. 169°-170.5°

The 6-acetic acids were prepared by way of the esters, Process E.

EXAMPLE 10

Process L

3-Phenyl-7-benzofuranacetic acid (2.5 g., 0.01 mole) is reduced with hydrogen gas using palladium on charcoal as catalyst and ethanol as solvent in a Brown hydrogenator. After the absorption of hydrogen stops, the reaction mixture is filtered, then the filtrate is evaporated in vacuo to a white solid. Recrystallization from a benzene-hexane mixture gives white crystals of 2,3-dihydro-3-phenyl-7-benzofuranacetic acid, m.p. 110.5°-111.5°.

______________________________________ Analysis: %C %H Calculated for C ₁₆ H ₁₄ O ₃ : 75.6 5.55 Found: 75.7 5.6 ______________________________________

EXAMPLE 11

Process N

Diethyl malonate (12.7 g., 0.079 mole) is dissolved in ethanol (40 ml.) and treated with sodium hydride (0.079 mole). 7-Chloromethyl-3-phenylbenzofuran (10.0 g., 0.0396 mole) is added and the mixture is heated to its reflux temperature and maintained at reflux for ten hours. Equal volumes of water and diethyl ether are added and the ether extracts are evaporated in vacuo. The residue is dissolved in ethanol and potassium hydroxide (16 g.) is added and the mixture is heated on a steam bath. A yellow solid forms rapidly, but heating is continued overnight. The solution is concentrated by evaporation in vacuo, then equal volumes of water and diethyl ether are added. The ether layer is washed with water, dried then evaporated to dryness. The residue is recrystallized from benzene to give 3-phenyl-7-benzofuranylmethylmalonic acid, m.p. 179°-180°.

3-Phenyl-7-benzofuranylmethylmalonic acid (1.8 g.) is heated to 180° dry, with an oil bath. Gas is evolved for about 10 minutes. The residue is recrystallized from a mixture of benzene-methanol to give 3-[7-(3-phenyl)benzofuranyl]-propionic acid, m.p. 161.5°-162.5°.

______________________________________ Analysis: %C %H Calculated for C ₁₃ H ₁₄ O ₃ : 76.7 5.3 Found: 76.7 5.3 ______________________________________

EXAMPLE 12

Process M, step (1) and (2)

7-Methyl-3-phenylbenzofuran is treated with an equimolar amount of bromine in carbon tetrachloride at room temperature until decolorized. The mixture is concentrated to dryness to remove hydrobromic acid and redissolved in carbon tetrachloride. To this solution is added an equimolar amount of N-bromosuccinimide and catalytic amounts (about one gram/mole of benzofuran) of cobalt stearate and tertiary-butyl hydroperoxide. The mixture is heated to reflux temperature and maintained at reflux for two hours while shining a bright floodlight directly upon the reaction mixture. The mixture is cooled, filtered to remove succinimide and concentrated in vacuo to a thick oil which slowly crystallizes on cooling to give 2-bromo-7-bromomethyl-3-phenylbenzofuran, m.p. 135°-138°.

EXAMPLE 13

Process M, steps (3) and (4)

A solution of 2-bromo-7-bromomethyl-3-phenylbenzofuran (35.6 g., 0.092 mole) dissolved in a minimum amount of dimethyl sulfoxide is added to a solution of sodium syanide (5.9 g., 0.12 mole) in dimethyl sulfoxide (50 ml.) and the mixture is heated at 50° to 60° for two hours. The dark solution is then poured over ice and the solid precipitate is collected by filtration. The product is 2-bromo-7-cyanomethyl-3-phenylbenzofuran.

To a mixture of 50% sodium hydroxide solution (35 ml.) and ethanol (100 ml.) is added 2-bromo-7-cyanomethyl-3-phenylbenzofuran (10 g., 0.032 mole). The mixture is heated to reflux temperature and maintained at reflux for about sixteen hours, then concentrated in vacuo. The residue is diluted with water, then extracted (washed) with diethyl ether. The aqueous layer is acidified with hydrochloric acid, yielding a precipitate which is collected by filtration and recrystallized twice from benzene-hexane mixtures to give 2-bromo-3-phenyl-7-benzofuranacetic acid, m.p. 162°-163.5°.

______________________________________ Analysis: %C %H Calculated for C ₁₆ H ₁₁ BrO ₃ : 58.0 3.3 Found: 58.5 3.2 ______________________________________

EXAMPLE 14

Process E, step (3)

Ethyl 3-phenyl-5-benzofuranacetate is prepared by cyclization of α-(4-carboethoxymethylphenoxy)acetophenone in five times its weight of polyphosphoric acid at 90° for 30 minutes. Distillation of the crude product gives the desired ester, b.p. ca. 190° C/0.01 mm, m.p. 43°-45°.

Heating 27 g. of ester overnight in 250 ml. of ethanol with 50 ml. of 50% sodium hydroxide gives 3-phenyl-5-benzofuranacetic acid, m.p. 131.5°-132° (after recrystallization from aqueous ethanol).

The required aryloxyacetophenone used as starting material is prepared according to the procedure of Example 1.

By the above sequence and starting with methyl p-hydroxyphenyl propionate there is obtained 3-phenyl-5-benzofuranpropionic acid, m.p. 99.5°-100°.

EXAMPLE 15

3-Phenyl-7-benzofuranacetic acid, 6.0 g., is heated for 15 minutes with 3.4 g. of sulfuryl chloride in 50 ml. of benzene then left at room temperature overnight to give 2-chloro-3-phenyl-7-benzofuranacetic acid which precipitates from the reaction mixture. Recrystallization from benzenehexane gives material of m.p. 150.5°-152°.

______________________________________ Analysis: %C %H Calculated for C ₁₆ H ₁₁ ClO ₃ : 67.1 3.9 Found: 67.3 3.8 ______________________________________

In a similar manner one can obtain 2-chloro-3-phenyl-5-benzofuranacetic acid, m.p. 155°-156.5° (benzene)

______________________________________ Analysis: %C %H Calculated for C ₁₆ H ₁₁ ClO ₃ : 67.1 3.9 Found: 67.1 3.8 ______________________________________

EXAMPLE 16

A solution of 1.0 g. of 5-methoxy-3-phenyl-7-benzofuranacetic acid in 5 ml. of acetic acid and 1 ml. of 47% hydriodic acid is heated at reflux for 16 hours to obtain the corresponding 5-hydroxy acid. It is isolated by precipitation with water, extraction into ether and then into sodium bicarbonate solution. Recrystallization from benzene gives 5-hydroxy-3-phenyl-7-benzofuranacetic acid, m.p. 197.5°-199°.

______________________________________ Analysis: %C %H Calculated for C ₁₆ H ₁₂ O ₄ : 71.6 4.5 Found: 71.1 4.6 ______________________________________

EXAMPLE 17

By the procedures illustrated in Examples 1-2 and 6-9 and starting with α-bromo-4-dimethylaminoacetophenone respectively, one obtains:

3-(4-methylthiophenyl)-7-benzofuranacetic acid

3-(4-methylsulfinylphenyl)-7-benzofuranacetic acid

3-(4-methylsulfonylphenyl)-7-benzofuranacetic acid

3-(3-trifluoromethylphenyl)-7-benzofuranacetic acid

3-(4-dimethylaminophenyl)-7-benzofuranacetic acid.

EXAMPLE 18

3-Phenyl-7-benzofuranacetic acid (0.5 g., 2 mmole) in dichloromethane (10 ml.) is treated with thionyl chloride (0.3 ml., 4 mmole). The mixture is heated to its reflux temperature and heated at reflux with stirring for 2.5 hours. Excess thionyl chloride is removed by twice adding benzene and evaporating under vacuum. Infrared spectral analysis of the product, 3-phenyl-7-benzofuranacetyl chloride, is consistent with the assigned structure. It is used without further purification.

The 3-phenyl-7-benzofuranacetyl chloride in diethyl ether (10 ml.) is added to excess diazomethane (8 mmole) in diethyl ether (17 ml.) at 0° over a 20 minute period. The solution is stirred an additional one hour at 0°, then evaporated under vacuum. The light yellow solid residue is dissolved in diethyl ether (2 ml.) and triturated with petroleum ether to provide a solid, light yellow product. The purity of the product, 3-phenyl-7-benzofuranacetyldiazomethane, is checked by thin layer chromatography on a silica gel plate and found to be good. Infrared spectral analysis of the product is consistent with the assigned structure.

A stirred solution of 3-phenyl-7-benzofuranacetyldiazomethane (0.20 g., 0.72 mmole) and 2N sulfuric acid (0.2 ml.) in dioxane (3 ml.) is heated at 60° to 65° for 20 minutes. The mixture is allowed to cool, then the white precipitate is separated by filtration, washed with water and recrystallized from ethanol to give hydroxymethyl 3-phenyl-7-benzofuranmethylketone, m.p. 119°-121°.

______________________________________ Analysis: %C %H Calculated for C ₁₇ H ₁₄ O ₃ : 76.68 5.30 Found: 76.2 5.38 ______________________________________

EXAMPLE 19

A solution of 3-(4-fluorophenyl)-7-benzofuranacetic acid (4.0 g., 14.8 mmole) in dichloromethane (100 ml.) is treated with thionyl chloride (2.2 ml., 30 mmole) and heated to its reflux temperature and maintained at reflux for three hours. The mixture is concentrated to an oil by evaporation under vacuum, dissolved in benzene (30 ml.) and evaporated under vacuum. The infrared spectrum of the product, 3-(4-fluorophenyl)-7-benzofuranacetyl chloride, is consistent with the assigned structure.

The acid chloride (4.3 g., 14.8 mmole) is dissolved in diethyl ether (80 ml.) and added dropwise to a cold (about 0° C.) solution of diazomethane (45 mmole) in diethyl ether (100 ml.) over a period of 30 minutes. The solution is stirred at 0° C. for two hours, then evaporated under vacuum. The residue is a light yellow solid, 3-(4-fluorophenyl)-7-benzofuranacetyldiazomethane. The infrared spectrum of the product is consistent with the assigned structure. The substituted diazomethane is then dissolved in dioxane (80 ml.) and treated with 0.1N aqueous perchloric acid (40 ml.) while stirring at 60°-65° for 1.5 hours. The mixture is evaporated under vacuum, then water is added and the mixture is again evaporated under vacuum. The white solid precipitate is separated by filtration and washed with water and petroleum ether. The solid is dissolved in diethyl ether and the solution is washed thrice with 50 ml. portions of 1N aqueous sodium carbonate and thrice with 50 ml. portions of saturated sodium chloride solution, then dried over anhydrous magnesium sulfate. The solution is filtered, then the solvent is removed by evaporation under vacuum. The residue is recrystallized from diethyl ether to provide pale yellow plates of 3-(4-fluorophenyl)-7-benzofuranmethyl hydroxymethyl ketone, m.p. 100°-101°.

______________________________________ Analysis: %C %H Calculated for C ₁₇ H ₁₃ FO ₃ : 71.83 4.61 Found: 72.11 4.86 ______________________________________

EXAMPLE 20

A stirred solution of 2-[7-(3-phenyl)benzofuranyl)]-propionic acid (5.0 g., 18.8 mmole), dichloromethane (100 ml.) and thionyl chloride (3 ml.) is heated to its reflux temperature and maintained at reflux for one day. The solution is evaporated under vacuum, the residue is twice dissolved in benzene and evaporated. The infrared spectrum of the product, 2-[7-(3-phenyl)benzofuranyl)]propionyl chloride (an oil), is consistent with the assigned structure.

The acid chloride is dissolved in diethyl ether (50 ml.) and added dropwise to a stirred cold (about 0°) solution of diazomethane (57 mmoles) in diethyl ether (125 ml.). After the addition the mixture is stirred for 0.5 hour at 0° and 0.5 hour at ambient temperature. The mixture is then evaporated under vacuum to a light yellow oil. The infrared spectrum of the product, 2-[7-(3-phenyl)benzofuranyl)]propionyldiazomethane, is consistent with the assigned structure.

The substituted diazomethane is then dissolved in dioxane (100 ml.) and treated with 0.5N aqueous perchloric acid (50 ml.) while stirring at about 65° C. for 0.75 hour. The solution is evaporated under vacuum, and the residue is extracted with diethyl ether. The ether extracts are washed thrice with 25 ml. portions of 1N aqueous sodium carbonate, then the ether solution is filtered, then evaporated under vacuum to provide a light yellow oil. The oil is chromatographed on a silica gel column, eluting with hexane, 50:50 hexane:chloroform, chloroform and 50:50 chloroform:methanol. Infrared spectral analysis of the fractions obtained shows that the later fractions are chiefly the desired product. Two recrystallizations from ethanol:petroleum ether mixtures give white solid product, hydroxymethyl 2-[7-(3-phenyl)benzofuranyl]ethylketone, m.p. 81°-85°.

______________________________________ Analysis: %C %H Calculated for C ₁₈ H ₁₆ O ₃ : 77.29 6.45 Found: 77.65 6.00 ______________________________________

Compounds of the invention prepared according to the methods specifically illustrated in Examples 18, 19 and 20 are shown in the table which includes Figures 17-34.