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Publication numberUS3655693 A
Publication typeGrant
Publication dateApr 11, 1972
Filing dateJun 25, 1969
Priority dateJun 25, 1969
Publication numberUS 3655693 A, US 3655693A, US-A-3655693, US3655693 A, US3655693A
InventorsTsung-Ying Shen, Gordon L Walford, Bruce E Witzel
Original AssigneeMerck & Co Inc
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Anti-inflammatory salicyclic acid derivatives
US 3655693 A
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Description  (OCR text may contain errors)

United States Patent 3,655,693 ANTI-INFLAMMATORY SALICYCLIC ACID DERIVATIVES Tsung-Ymg Shen, Bruce E. Witzel, and Gordon L. Walford, Westfield, N.J., assignors to Merck & Co., Inc., Rahway, NJ. No Drawing. Filed June 25, 1969, Ser. No. 836,582 Int. Cl. A61k 27/00; C07d 63/12, 63/14 US. Cl. 260-3322 A 6 Claims ABSTRACT OF THE DISCLOSURE Salicylic acid derivatives and their non-toxic pharmaceutically acceptable salts, esters and amides are claimed. Also encompassed is the treatment of inflammation with said derivatives.

This invention relates to novel anti-inflammatory compounds. More particularly, it relates to acids of the formula:


(Formula I) S or 0; wherein R is H or lower alkyl R is H; acyl (preferably lowe'r acyl such as formyl, acetyl, propionyl, butyryl etc.); alkyl (preferably lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc. alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexoxycarbonyl, etc.).

R may be hydrogen, halogen (such as chloro, bromo, fluoro, or iodo, preferably fluoro or chloro), haloalkyl (preferably haloloweralkyl such as trifluoromethyl, etc.), alkyl (preferably loweralkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), cycloalkyl (eq. cyclobutyl, cyclopentyl, cyclopropyl, cyclohexyl and cycloheptyl) or alkoxy (preferably loweralkoxy such as methoxy, ethoxy, isopropoxy or butoxy, etc.).

X may be hydrogen, alkyl, (preferably loweralkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), hydroxy, alkoxy (preferably loweralkoxy such as methoXy, ethoxy, isopropoxy or butoxy, etc.), acyloxy (such as benzoyloxy, acetoxy or propionoxy), halogen (such as chloro, bromo, fluoro or iodo, preferably fluoro or chloro), haloalkyl (preferably haloloweralkyl such as trifluoromethyl, etc.), nitro, amino, alkylamino (preferably loweralkylamino such as methylamino, propylamino, pentylamino, etc.), diloweralkylamino (dimethylamino, dibutylamino, propylpentylamino, etc.), acylamino (preferably loweracylamino such as formylamino, acetylamino, propionylamino, butrylamino, etc.), mercapto, alkylmercapto (preferably loweralkylrnercapto such as methylmercapto, ethylmercapto, etc.), alkylsulfinyl (preferably loweralkylsulfinyl such as methylsulfinyl, ethylsulfinyl, butylsulfinyl, etc.), alkylsulfonyl (preferably loweralkylsulfonyl such as methylsulfonyl, ethylsul-fony l, butylsulfonyl, etc.), sulfonamido, sulfinylamido, aminoalkyl,

3,655,693 Patented Apr. 11, 1972 alkylaminoalkyl (preferably loweralkylaminoloweralkyl such as methylaminomethyl, ethylaminomethyl, etc. dialkylaminoalkyl (as illustrated by dimethylammomethyl, me'thylethylaminomethyl) hydroxyalkyl (preferably hydroxyloweralkyl such as hydroxyrnethyl hydroxyethyl, hydroxypropyl, etc.), acylarninomethyl, alkoxyalkyl (preferably loweralkoxyoweralkyl such as methoxymethyl, methoxyethy l, ethoxyethyl, ethoxypropyl, etc.), mercaptoalkyl (preferably mercaptoloweralkyl such as mercaptomethyl, mercaptoethyl, etc.),

alkylmercaptoalkyl (preferably loweralkylmercaptolower alkyl such as methylmercaptomethyl, ethylmercaptoethyl, ethylmercaptopropyl, etc.), cyano, carboxy, carboalkoxy (carbomethoxy, carboethoxy, etc.), carbamoyl, aryl (such as phenyl, halophenyl, tolyl, salicyl), aralkyl such as benzyl, aryloxy, aralkoxy and acyl (preferably loweracyl such as formyl, acetyl and butyryl, etc.).

The preferred class of acids are of the salicylic configuration where the OR is ortho to the COOH; the bridging member A is attached to the 4 or 5 position of the benzene ring and to the 2 or 3 position of the livemembered ring above.

The acid derivatives of the above description possess a high degree of anti-inflammatory activity. They are of valuein the treatment of arthritic and dermatological disorders or like conditions responsive to anti-inflammatory drugs. Included within this category are diseases such as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic (fever. The acid derivatives als possess a useful degree of analgesic and anti-pyretic activity.

For these purposes the compounds of the invention may be administered orally, topically, parenterally or rectally in formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles. In addition tothe treatment of warm-blooded animals such as mice, rats, etc., the compounds of the invention are effective in the treatment of humans.

The non-toxic pharmaceutical carriers indicated above include either solids or liquids. Exemplary of solid carriers are lactose, corn starch, gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba, sucrose, agar, pectin, Cab-o-sil, and acacia. Exemplary of liquid carriers are peanut oil, olive oil, sesame oil and water. Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositions can be used. For example, if a solid carrier is used, the compositions may take the form of tablets, capsules, powders, troches or lozenges, prepared by standard pharmaceutical techniques. If a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a syrup or a liquid suspension. Suppositories may be prepared in a conventional manner.

Thecompounds of Formula I are present in an amount suflicie'nt to treat inflammation. Advantageously, the composition will contain the active ingredient, in an amount of from about 1 mg. to mg. per kg. body weight per day (50 mg. to 7 g. per patient per day), preferably from about 2 mg. to 50 mg./kg. body weight per day (100 mg. to 3 g. per patient per day).

The preferred method of treatment comprises internal administration to a patient (animal or human), a compound of Formula I, admixed with a non-toxic pharmaceutical carrier such as exemplified above. The compounds of Formula I will be administered in an amount of from 1 mg. to 100 mg./kg. body weight per day, preferably from about 2 mg. to about 50 mg. per kilogram body weight per day and especially from 4 mg. to 20 mg./kg. body weight per day. The most rapid and effective antiinflammatory effect is obtained from oral administration of a daily dosage of from about 4 to 20 mg./kg. per day. It should be understood, however, that although preferred dosage ranges are given, the dose level for a particular patient depends upon the activity of the specific compound employed. Also many other factors that modify the actions of drugs will be taken into account by those skilled in the art in the therapeutic use of the medicinal agents of Formula I; for example, age, body Weight, sex, diet, time of administration, route of administration, rate of excretion, drug combination, reaction sensitivities and severity of the particular disease.

The compounds of the invention may be produced utilizing the following starting materials:

u-a) Y Members of this class such as ILELQM ELKQQH are well known and convenient techniques for their preparation are available to the skilled artisan.

In addition to the above, a number of processes for the preparation of the phenolic starting materials from available reactants may be presented as follows:

wherein X, R and R are as defined above.

The sodium cyclopentadienyl material is added at room temperature to the phenol and the mixtures stirred for five hours; the residue is extracted with chloroform; the chloroform extract is dried, filtered and concentrated to produce the product.

Y onion Q-on a U-a) CHz--0H Y Y and R are as indicated above.

X=hydrogen, alkyl, halogen, haloal'kyl, N0 acylamino,

alkylmercapto, alkylsulfonyl, alkylsulfinyl, acyl, aryloxy, aryl, aralkyl, carboalkoxy and acylarninomethyl. The phenol and S-membered alcohol mixture is heated with HCl at 80 C. for six hours; an aqueous layer is separated, acidified and extracted with ether to produce the product.

X is as set forth in (b) above. Y=O or S R and R are as defined above.

The preferred compounds are those wherein the group is joined to the 2 or 3 position. When joined to the 2-position it is desirable for the 3, 4 or s-position to contain an H, halo, or alkyl.

(1) Acylation: To the mixture of the 5-membered ring and the benzoyl chloride in benzene is added tin tetrachloride; the mixture is stirred; water is added; the layers separated; the benzene layer containing the desired product is Washed, dried and concentrated in vacuo.

Conventional acylation'techniques may be employed in the above reaction including the use of catalysts such as AlCl BF ZnCl etc. I may also be employed as the acylation catalyst. The acylation may also be accomplished utilizing the acylating acid in phosphoric acid or P 0 in addition to acid chlorides. Also encompassed within this class are the tetraacyloxysilanes.

(2) The ketone is heated with hydrazine hydrate to form the hydrazone; diethylene glycol and KOH are added; the mixture is heated, then added to Water and extracted with benzene. The benzene extracts are washed with water, dried and concentrated in vacuo and the residual material distilled or chromatographed.

X and R are as defined above.

(1) Acylation: The pyrrole-grignard mixture is cooled; the acylating agent added; acidified; the ether layer separated, washed, dried, filtered and the residue distilled or chromatographed.

(2) Reduction in accordance with section (c) (2).

R =lower alkyl; X, Y and R are as defined above.

Methylene chloride is added to the alkoxy material followed by the addition of boron-tribromide at low temperatures; the mixture is stirred, brought to room temperature; acid added; the layers are separated; the methylene chloride mixture dried, filtered, concentrated in vacuo; the residue is chromatographed on silica gel.

Carboxylation of the starting materials of the formula:

H mas-H prepared in accordance with sections (a), (b), (c), (d) and (e), proceeds as follows:

OH ian-H A X is hydrogen, alkyl, halogen, haloalkyl, N0 acylamino, alkoxy, alkylmercapto, alkylsulfonyl, alkylsulfinyl, acyl, aryloxy, aryl, aralkyl, carboalkoxy, and -acylaminomethyl.

Y, A, and R are as defined above.

An economical method for the carboxylation of the starting material involves mixing the starting material with a carbonate such as potassium carbonate in a high pressure CO atmosphere; heat is applied; the mixture cooled; added to water; filtered; the filtrate is acidified to yield the carboxylated product.

In addition, carboxylation may be effected by the use of the Grignard reagent with carbon dioxide in dry ether, followed by hydrolysis. Furthermore, the technique known as the Wanklyn reaction may be employed in this regard.

The following examples are given for the purpose of illustration and not by way of limitation:

EXAMPLE 1 Preparation of 2(p-anisoyl)-5-fluorothiophene (A) To a solution of Z-fiuorothiophene (0.1 m.) and p-methoxybenzoyl chloride (0.1 m.) in dry benzene (40 ml.) at 20-25 C. is added dropwise With stirring tin tetrachloride (13 g.), the mixture allowed to stir at room temperature for three hours, water added carefully, the layers separated, the benzene layer washed Well with water, dried, concentrated in vacuo, and the residual material chromatographed on a silica gel column using an etherpetroleum ether system (v./v. 0-80% ether) as eluant to yield 2-(p-anisoyl)-5-fluorothiophene.

(B) When m-methoxybenzoyl chloride, 4-methoxy-2- methylbenzoyl chloride, 2-chloro-4-methoxybenzoyl chloride, 2-fiuoro-4-methoxybenzoyl chloride, 4-methoxy-2-trifiuoromethylbenzoyl chloride, 2-methoxy-4-benzyloxybenzoyl chloride, or p-benzyloxybenzoyl chloride is used in place of p-methoxybenzoyl chloride in the above reaaction, the corresponding 5 (substituted-benzoyl)-2-fluorothiophene is obtained.

(C) When 2-chlorothiophene, 2-bromothiophene, thiophene, Z-methylthiophene, 2-acetylthiophene, 2-benzylthiophene, 2-phenylthiophene, 2-methylmercaptohthiophene, Z-acetamidothiophene, 3-fluorothiophene, 2 (and 3) methylsulfonylthiophene, 2,5-dirnethylthiophene, 2-acetamidomethylthiophene, 2,3,5-trimethylthiophene, furan, 2 (and 3) fluorofuran, 2 (and 3) chlorofuran, 2-bromofuran, 2-acetylfuran, 2,3,5-trimethylfuran, 2-phenoxyfuran, Z-nitrofuran, Z-trifluoromethylfuran, Z-carbomethoxyfuran, 2-carbomethoxythiophene or 2,5-dichlorothiophene are used in place of 2-fluorothiophene in the above acylations, the corresponding (substituted-benzoyl)-substitutedthiophenes and furans are obtained.

EXAMPLE 2 Preparation of a-(2-phenylcyclopenta-(2,4-dieny1)- p-cresol To a mixture of 2-phenylcyclopentadienyl sodium (obtained from the parent compound with sodium in ethanol) (0.04 m.) is added p-(chloromethyl)-phenol (0.04 m.) during one hour at 25 C. and the resulting mixture allowed to stir for 5 hours. The ethanol is removed in vacuo, the residue extracted with chloroform, the chloroform extract dried, filtered and concentrated in vacuo to yield a-(2-phenylcyclopenta-(2,4)-dienyl)-p-cresol..

When a substituted cyclopentadienyl is employed in the above reaction in place of the 2-phenylcyclopentadienyl, the corresponding substituted a-(cyclopenta- 2,4)-dieny1- p-cresols are obtained. Representative members of this class include: 2-fluorocyclopentadienyl, 3-methylcyclopentadienyl and 3-ethoxycyclopentadienyl.

EXAMPLE 3 Preparation of 2-(p-methoxybenzoyl)-l-methylpyrrole N-methylpyrrole (21 g.) is added dropwise to an etheralgrignard mixture prepared from magnesium (6.2 g.) and ethylbromide (31 g.). When evolution of ethane has ceased, the pyrrole-grignard mixture is ice-cooled, and pmethoxybenzoyl chloride (36.3 g.) added dropwise; after the addition the mixture is allowed to stir at ambient temperatures, ice water added cautiously, the aqueous mixture acidified with sulfuric acid, the ether layer separated, washed with dilute sulfuric acid and Water until the washes remain neutral; the ether solution is dried, filtered and the residue distilled under reduced pressure to yield 2-(p-methoxybenzoyl)-1-methylpyrrole.

The acylating agents indicated in Example 1 are applicable for this reaction. For example, when p-benzyloxybenzoyl chloride is used in the above reaction, 2-(p-benyloxybenzoyl)-1-methylpyrrole is obtained.

In addition to N-methylpyrrole, the above procedure is applicable to pyrroles wherein alkyl radicals, such as ethyl and butyl, may be attached to the nitrogen atom.

Furthermore, substituted pyrroles wherein the substituent represents the radical X, as defined above, are contemplated in the acylation relation set forth above. Accordingly, a pyrrole-Grignard mixture wherein the pyrrole is exemplified by the following: N-ethyl 2-fluoropyrrole; N-methyl 2-phenylpyrrole; N-methyl-Z-methylpyrrole will result in the production of the corresponding acylated material.

EXAMPLE 4 Preparation of p-(S-fluorofurfuryD-phenol A mixtureof phenol (0.1 ml.), S-fluorofurfuryl alcohol (0.1 m.), and 1 N hydrochloric acid (0.15 ml.) is heated at for 6 hours, the mixture distributed between etherdilute sodium hydroxide solution, the aqueous layer sepparated, acidified, extracted well with either and the ether extracts iractionally distilled to yield p-(5-fiuorofurfuryl)- phenol.

(a) The above procedure is applicable wherein the substituted phenols contemplated by the invention are utilized in .place of phenol illustrated in the example.

For example, when resorcinol monomethyl ether, mcresol, meta-fluoroor metal-chlorophenol is used in placed of phenol, the correspondingly substituted compound is obtained. Accordingly, meta-fluorophenol shall result in p- (S-fluorofurfuryl) m-fiuorophenol, etc.

In addition to the use of substituted furfuryl alcohols other than the S-fluoro illustrated above, the reaction is applicable for the preparation of phenols utilizing the various thiophenes and pyrroles contemplated by the invention.

EXAMPLE 5 Preparation of 2-fluoro-5- (p-methoxybenzyl) -thiophene A mixture of 2-fluoro-5-(p-methoxybenzoyl)-thiophene (0.1 In.) prepared according to Example 1 and hydrazine hydrate (0.1 m.) in methanol is heated to form the hydrazone, the methanol is removed and diethylene glycol (50 ml.) added, then potassium hydroxide pellets (0.2 m.) and the mixture heated until gas evolution ceases. On cooling, the mixture is added to water (300 ml.) and the mixture extracted with benzene. The benzene extracts are washed well with water, dried, concentrated in vacuo, and the residual materials distilled under reduced pressure or chromatographed (silica gel column; ether-petroleum ether system (v./v. -80% ether)) to yield 2-fiuoro-5-(p-methoxybenzyl -thiopl'1ene.

It may be noted that reduction may also be carried out via the well known Clementson procedure utilizing amalgamated zinc and hydrochloric acid, in addition to other conventional reduction techniques.

When the ketones of Examples 1 and 3 are reduced as above, the corre spondingly-substituted benzyl thiophenes, furans and pyrroles are obtained.

For example, reduction of 5-chloro-2-(m-methoxybenzoyl)-thiophene; 2,4,5-trimethyl 3-(2-chloro-4-methoxybenzoy1)-furan and 2-(p-methoxybenzoyl)-l-methylpyrrole in accordance with the above process results in the production of the following materials: S-chloro-Z-(mmethoxybenzyl)thiophene; 2,4,5-trimethyl-3-(2-chloro-4- methoxybenzyDfuran and 2-(p-methoxybenzyl)-1-methylpyrrole.

It should be noted that in addition to reduction of the corresponding benzoyl derivative, direct benzylation may be successfully employed.

EXAMPLE 6 Preparation of p-(S-fluorothenoyl)-phenol A mixture of 2-(p-benzyloxybenzoyl)-5-fluorothiophene (0.01 m.), 5% Pd/C (2 g.) and ethanol (50 ml.) is shaken in a 40 p. s.i. hydrogen atmosphere at room temperature until the theoretical amount (0.01 m.) of hydrogen has been adsorbed. The mixture is filtered and the solvent removed in vacuo to yield p-(5-fluorothenoyl)- phenol.

When the benzyl ethers of Examples 1, 3 and 5 are treated accordingly, the corresponding phenols are obtained.

EXAMPLE 7 Preparation of Z-fiuoro-S-(p-hydroxybenzoyl)- thiophene To a cold (-60) mixture of 2 fluoro 5 (p-methoxybenzoyD-thiophene (0.03 m.) and methylene chloride (50 ml.), which is stirred and protected from moisture, is added boron tribromide (0.01 m.) and the resultant mixture allowed to warm slowly to room temperature. After stirring several hours, a minimum of 10% aqueous sodium hydroxide is added to hydrolyze the complex. The mixture is then acidified with 2% hydrochloric acid and the layers separated. The methylene chloride mixture is dried, filtered, concentrated in vacuo, and the residue chromatographed on silica gel using an etherpetroleum ether system as eluant to yield 2-fiuoro-5-(phydroxy-benzoyl) -thiophene.

When the ethers of Examples 1, 3 and 5 are reacted with =boron tribromide, the corresponding phenols are obtained.

EXAMPLE 8 Preparation of 5-(5'fluoro-2-thenoyl)- salicyclic acid An intimately ground mixture of 2-fluoro 5 (p-hy- 'droxybenzoyl)thiophene (5 g.) and anhydrous potassium carbonate (15 g.) is heated at 200 C. in a 1200-1400 p.s.i. carbon dioxide atmosphere for 8 hours. The mixture is cooled, added to water 300 ml.), allowed to stir, filtered, and the filtrate acidified with dilute hydrochloric acid to yield 5-(5'-fluoro-2'-thenoyl)-salicylic acid.

Purification may be elfected via recrystallization or via chromatography of the methyl ester.

When the phenols of Examples 4, 5, and 6 are used in the above procedure, the corresponding salicylic acid is obtained.

A representative list of salicylic acids are as follows:

5- 5-phenyl-2-cyc10penta( 2,4 )dienylmethyl) salicylic acid 5-(5-fluoro-2-cyclopenta(2,4-dienylmethyl)- salicylic acid 5- (5-nitro-2-cyclopenta 2,4) dienylmethyl) salicylic acid 5- 5-acetyl-2-furoyl -salicylic acid 5- 5-cyclobutyl-2-furylmethyl) -salicylic acid 4- (5-ethyl-2-thienylmethyl -salicylic acid 4- (5-nitro-2-thenoyl) -salicylic acid 5- S-methylmerc apto-3-thenoyl) -salicylic acid 5- (S-fluoro-Z-thienylmethyl) salicylic acid 5 5-trifluoromethy1-2-N-methylpyrrylmethyl) salicylic acid 2- 3 -car-boxy-4'-hydroxyb enzoyl) -5-fluoro-N- methylpyrrole.

EXAMPLE 9 Preparation of methyl 5-(5'-cyano-2-thenoyl) salicylate A mixture of methyl 5 (5' bromo 2' thenoyl)- salicylate (0.02 m.), cuprous cyanide (0.03 m.), and N-methylpyrrolidone is de-aerated, covered with a nitrogen atmosphere and heated slowly to 180 (3., the mixture is kept at this temperature for 3 hrs. allowed to cool, partitioned between benzene-7% hydrochloric acid containing ferric chloride (0.03 m.), the 'benzene layer then separated, dried, concentrated and the residue chromatographed on a silica gel column using an etherpetroleum ether system as eluant (v./v. 580% ether) to yield methyl 5-(5-cyano2-thenoyl)salicylate.

EXAMPLE 10 Preparation of methyl 2-acetoxy 5(5-bromomethy1- 2-thenoyl)benzoate A mixture of methyl 2 acetoxy 5(5' methyl-2'- thenoyl)benzoate (0.05 m.), N-bromosuccinimide (0.05 m.), carbon tetrachloride (500 ml.) and dibenzoyl peroxide (0.002 m.) is refluxed gently for 3 hrs., and cooled. The succinimide is removed by filtration, and the solvent removed in vacuo to yield methyl 2-acetoxy-5(5-bromomethyl-2'-thenoyl)benzoate.

EXAMPLE 1 1 Preparation of methyl 5- (5'-hydroxymethyl-2'- thenoyl) salicylate A mixture of methyl 2-acetoxy 5(5 hromomethyl- 2-thenoyl)benzoate (0.01 m.), silver acetate (0.01 m.)

and acetic acid 30 ml.) is heated gently for three hours, cooled, filtered, and the filtrate concentrated in vacuo to a residue of crude methyl 2 acetoxy 5 (5' acetoxymethylthenoyl)-benzoate. Anhydrous methanol (50 ml.) and p-toluenesulfonic acid (0.3 g.) is added and the mixture refluxed for three hours, concentrated, distributed between water-chloroform. The chloroform layer is dried, concentrated, and the contents chromatographed on a silica gel column using an ether-petroleum ether system (v./v. -100% ether) as eluant yielding methyl -(5'- hydroxymethyl-2'-thenoyl) salicylate.

When potassium thiolacetate is used in place of silver acetate in the above reaction; methyl 5-(5 mercaptomethyl-2-thenoyl)salicylate is obtained.

EXAMPLE 12 Preparation of methyl 5-(5'-methoxymethyl-2- thenoyl) salicylate Methyl 2 acetoxy 5 (5'-bromomethyl-2-thenoyl)- benzoate (0.01 m.) is added to a stirred solution of sodium methoxide (0.02 m.) in anhydrous methanol. The mixture is refluxed gently for one hour, cooled, dilute hydrochloric acid added to neutralize the mixture and the solvents removed in vacuo. The residue is chromatographed on a silica gel column using an ether-petroleum ether system (v./v. 0-40% ether) as eluant to yield methyl 5 (5 methoxymethyl 2 thenoyl)- salicylate.

When potassium methylmercaptide is used in place of sodium methoxide, methyl 5 (5' methylthiomethyl-2'- thenoyl)salicylate is obtained.

EXAMPLE 13 Preparation of methyl 5-(5-dimethylaminomethyl-2'- thenoyl)-salicylate Methyl 2 acetoxy-5-(5'-bromomethyl-2'-thenoyl)-benzoate (0.002 m.) is heated in methanolic dimethylamine. The solvent is removed in vacuo and the residue taken up in 2.5 N hydrochloric acid, filtered, basified, and the resultant 5-(S'dimethylaminomethyl-Z-thenoyl)salicylate collected.

When methanolic ammonia is used in place of the dimethylamine in the above reaction, the corresponding 5- (5-aminomethyl-2'-thenoyl)-salicylate is obtained.

EXAMPLE 14 Preparation of 2-acetoxy-5-(5'-chloro-2-thenoyl)- benzoic acid To a mixture of 5-(5'-chloro-2'-thenoyl)salicylic acid (0.04 m.) in anhydrous pyridine (15 ml.) is added acetic anhydride (28 ml.) and the resultant mixture heated on the steam cone for 1.5 hrs. The mixture is kept free from moisture during this time. On cooling, the mixture is added to a stirred 500 ml. portion of water. The aqueous system is then extracted well with chloroform, the chloroform extracts washed with 1 N hydrochloric acid, water, and dried over anhydrous magnesium sulfate. Concentration of the filtered solution yields 2-acetoxy-5-(5'-chloro-2'-thenoyl)- benzoic acid.

When propionic or butyric anhydride is used in place of acetic anhydride in the above example, the corresponding propionoxy or butyroxy compounds are obtained.

EXAMPLE 15 Preparation of methyl 2-carboxy-4-(5'-fiuorofurfuryl)- phenyl carbonate To a mixture of 5-(5-fluorofurfuryl)-salicylic acid 0.01 m.), dimethylaniline (0.02 m.) and benzene (30 ml.) is added methyl chloroformate (0.011 In.) over one hour with constant shaking and cooling. When the odor of the chlorocarbonate ils essentially absent, hydrochloric acid (1 N, 100 ml.) is added and the mixture filtered. The benzene layer is then separated, dried, filtered, and the solvent removed in vacuo to yield methyl 2-carboxy-4-(5'-fluorofurfuryD-phenyl carbonate.

EXAMPLE 16 Preparation of 2( 3-carboxy-4-methoxybenzyl)-5- fluorothiophene To a mixture of 2(3 carboxy-4'-hydroxybenzyl)-5- fluorothiophene (0.01 m.) in 2 N sodium hydroxide solution at C. is added dimethyl sulfate (0.10 In.) in small portions over ten hours, the mixture being kept basic throughout the addition. Water is added, the mixture filter'ed, the filtrate acidified and 2(3'-carboxy-4'-methoxybenzyl)-5-fiuorothiophene collected.

EXAMPLE 17 Preparation of methyl 5-(5-methoxyfuroyl)-salicylate A mixture of 10 g. of methyl 5-(5-bromo-2-furoyl)- salicylate and 125 ml. of 2.5 M sodium methoxide in absolute methanol is heated for 30 mins. at ca. 90 in a stoppered bottle, the excess methanol removed in vacuo, dilute hydrochloric acid added and the mixture extracted with chloroform. Concentration of the chloroform solution yields methyl 5-(5'-methoxyfuroyl)-salicylate.

When an equivalent amount of sodium benzylate in methanol is used in place of sodium methoxide, the 5- benzyloxy analog is obtained.

When the salicylates of the invention are reacted with silver acetate in acetic acid, the corresponding acetoxy analogs are obtained.

When reacted with excess methanolic dimethylamine, the S-dimethylamino analog is obtained.

EXAMPLE 18 Preparation of methyl 5-(5'-carbamyl-2-thenoyl)- salicylate A mixture of methyl 5-(5'-cyano-2-thenoyl)-salicylate (0.02 m.) and polyphosphoric acid (50 ml.) is heated on a steam cone for 2 hours, cooled, added to water and the aqueous mixture extracted well with chloroform. The chloroform layer is dried, filtered, and then concentrated in vacuo to yield crude methyl 5-(5-carbamyl-2-thenoyl)- salicylate, which may be purified via column chromatography or recrystallization of the corresponding salicylic acid.

EXAMPLE 19 Preparation of 5-(5-carboxy-2-thenoyl)-salicylic acid To a mixture of 5-(5'-canbomethoxy-2-thenoyl)-salicylic acid (0.01 m.) and methanol ml.) is added with stirring sodium hydroxide (0.06 m.) and water (15 ml.). The resultant mixture is stirred overnight at room temperature, diluted with water (200 ml.), filtered and the filtrate acidified with 2.5 N hydrochloric acid. The 5-(5'- carboxy-2-thenoyl)-salicylic acid is then collected.

The esters of the invention may be obtained by esterification with an appropriate alcohol in an inert solvent in the presence of an acid catalyst such as an aryl sulfonic acid. Alternatively, esterification may be effected utilizing a diazomethane reagent. Further exemplification of esterification procedures is indicated in the following examples:

EXAMPLE 20A Preparation of methyl 5(5'-fluoro-2'-thenoyl)-salicylate 5(5-fluoro-2'-thenoyl)salicylic acid (0.01 m.) is added to a solution of anhydrous methanol (25 ml.) containing ca. 200 mg. of anhydrous hydrogen chloride. The resultant mixture is heated under gentle reflux for several hours, the solvent removed in vacuo and the residue partitioned between chloroform-dilute sodium bicarbonate solution and the layers are separated. The chloroform layer is dried over anhydrous sodium sulfate, filtered and evaporated to leave methyl 5(5-fluoro-2-thenoyl)-salicylate.

1 1 When ethanol, propanol, isopropanol, or butanol is used in place of methanol in the above reaction, the corresponding ester is produced.

When the salicylic acids of Example 8 are used in place of (5'-fiuoro-2'-thenoyl)-salicylic acid in the above example, the corresponding esters are obtained.

EXAMPLE 20B Preparation of methyl 2-acetoxy-5-(5-fiuoro-2'-thenoy1)- benzoic acid Diazomethane in methylene chloride is added to an ice cooled mixture of 2-acetoxy-5-(5'-fluoro2'-thenoyl) benzoic acid in methylene chloride until nitrogen evolution ceases and the color of diazomethane persists, The solvent is then removed in vacuo to yield methyl 2- acetoxy-S- 5'-fluoro-2-thenoyl -benzoate.

When other diazo compounds are used in place of diazornethane in the above example, for example, diazoethane, phenyldiazomethane, etc., the corresponding esters are obtained.

EXAMPLE 21 Preparation of phenyl 5(5'-fluoro-2'-furfuryl) salicylate To a mixture of polypho'sphate esters (P.P.E.) (15 equiv.) in chloroform is added one equivalent each of 5(5'-fluoro-2'-furfuryl)salicylic acid and phenol, and the resultant mixture heated gently for 30 minutes. The chloroform mixture is cooled, washed with dilute bicarbonate solution. The chloroform layer is then dried, filtered and evaporated in vacuo to yield phenyl 5(5'-fiuoro-2'-furfuryl salicylate.

When the salicylic acids of Example 8 are used in the above reaction, the corresponding phenyl esters are obtained.

EXAMPLE 22 Preparation of 5-(5-nitro-2'-furfuryl)salicylanilide A mixture of phenyl 5-(5'-nitro-2'-furfuryl)salicylate (0.1 m.), aniline (0.1 m.), and l-methylnaphthalene (50 ml.) is heated slowly to 230 C. and kept at this temperature until phenol has stopped distilling. Charcoal (2 g.) is then added and then 20 ml. additional methylnaphthalene added. The mixture is heated for min., filtered hot, and cooled. The collected anilide is then recrystallized yielding pure 5-(5'-nitro-2-furfuryl)salicylanilide.

EXAMPLE 23 Preparation of 5-(5-fiuoro-N-methylpyrrylmethyl) salicylamide A mixture of methyl 5-(5'-fluoro-N-methylpyrrylmethyl)salicylate and concentrated ammonium hydroxide five-fold excess )is heated at 100 C. in a sealed tube for six hours. After cooling water is added and the 5-(5'- fluoro-N-methylpyrrylmethyl)'salicylamide collected.

When monomethylamine, dimethylamine, ethylamine, diethylamine, morpholine, piperidine, etc. are used in place of ammonium hydroxide, the corresponding amides are obtained.

EXAMPLE 24 Preparation of N,N-diethylaminoethyl 5-(5-phenyl- 2-cyclopenta (2,4) dienylmethyl) salicylate To a mixture of 5-,5'-phenyl-2'-cyclopenta(2,4)dienylmethyl)salicy1ic acid (0.01 m.) and N,N-diethylethanolamine (0.01 m.) in anhydrous tetrahydrofuran (100 m1.) is added a solution of dicyclohexylcarbodiimide (0.01 m.) in a minimum of the same solvent. The mixture is stoppered, shaken well, and allowed to stand overnight. The precipitated dicyclohexylurea is removed by filtration; the filtrate concentrated in vacuo and the residue partitioned between ether and 1 N hydrochloric acid. The layers are separated and the aqueous layer washed once with fresh ether and neutralized with saturated sodium 12 bicarbonate solution. Extraction with chloroform, fol lowed by removal of the chloroform in vacuo (high vacuum pump to remove traces of starting amine) yields N,N diethylaminoethyl 5-(5'-phenyl-2-cyclopenta(2,4) dienylmethyl)salicyclate.

EXAMPLE 25 Preparation of sodium 5(5'-methyl-2'-thienylmethyl) salicylate Solutions of 5 (5-methyl-2'-thienylmethy1)salicylic acid in methanol and sodium hydroxide (1 equiv.) in water are mixed, heated for solution, filtered, and the filtrate concentrated in vacuo to obtain sodium 5-(5'- methyl-2'-thienylmethyl) salicylate.

When potassium hydroxide is used in place of sodium hydroxide in the above example, the corresponding potassium salt is obtained.

When two equivalents of the above bases are used, the corresponding disodioand dipotassio-salts are obtained.

EXAMPLE 26 Preparation of diethylaminoethanol salt of 5-(5'- chloro-2'-furfuryl)salicyclic acid N,N-diethylethanolamine (0.001 m.) in ether (5 ml.) is added to a stirred solution of 5-(5-chloro-2'-furfuryl) salicyclic acid (0.001 m.) in chloroform-methanol, the resultant mixture allowed to stir for one hour, the salt collected or the solvent removed in vacuo to yield the diethylaminoethanol salt of 5-(5-chloro-2-furfuryl)salicyclic acid.

When piperidene, morpholine, triethylamine, N-methylpiperidine, N-methylmorpholine, tributyl amine or other organic amines are used in place of diethylethanolamine in the above example, the corresponding salt is obtained.

What is claimed is:

1. A compound of the formula:

wherein 2. The compound of claim 1 wherein is attached to the 4 or 5 position of the benzene ring.

3. Methyl 5-(5-cyano-2'-thenoyl)salicylate according to claim 1.

4. 5-(5'-fluoro-2-thienylmethyllsalicyclic acid according to claim 1.

5. 5-(5'-carboxy 2-thenoyl)salicylic acid according to claim 1.

6. Methyl 5-(5'-carbamoyl-2-thienylmethyl')salicylate according to claim 1.

(References on following page) 13 14 References Cited 294.7 D, 294.7 B, 326.3, 326.5 s, 326.5 SF, 326.5 J, 326.5 L, 326.5 M, 332.2 0, 332.3 R, 347.2, 347.3, 347.4, UNITED STATES PATENTS 347.5, 347.7, 347.3, 463,465 D, 470, 471 R, 471 A, 471 0, 3,558,641 1/1971 Safe et 260295 473 R, 474, 476 R, 476 c, 488 CD, 516, 513 R, 518A, 5 519, 520, 551 s, 556 A, 559 T, 559 s, 559 A, 559 R, HENRY LES, Pnmary Exammer 562 R, 570.5 CA, 570.8 R, 570.9, 574, 575, 591, 612R, 0. M. SHURKO, Assistant Examiner 612 D, 607A, 609 R, 621 R, 622.5, 623 R, 623 D, 613 R, 613 D, 624 R; 424-230, 234,248, 268, 274, 275, 285, us. 01. X.R. 301, 308, 309, 311, 317; 425-319, 320, 324

260--247.1, 247.2 R, 247.2 A, 247.2 B, 247.5 R, 247.7 c, 10 247.7 G, 247.7 H, 293.4 G, 293.4 R, 293.4 E, 294 R, 294 1), 294 A, 294.3 R, 294.3 B, 294.3 E, 294.3 A,

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