SUBSTITUTED SALICYLIC ACID DERIVATIVES AND PROCESSES FOR THEIR PREPARATION

PATENT SPECIFICATION (¹¹) 1272190 NO DRAWINGS

(21) Application No. 29667/70 (22) Filed 18 June 1970

131) Convention Application No. 836582 (32) Filed 25 June 1969

(31) Convention Application No. 30290 (32) Filed 20 April 1970 in

(33) United States of America (US)

(45) Complete Specification published 26 April 1972

(51) International Classification C07D 5/16 C07C 65/00 69/76 79/46

87/06 91/06101/42 C07D 27/26 29/02 57/00 63/12

87/22 99/02

(52) Index at acceptance

C2C 172-194-284 174-271-276 175-193-286

17X-186-272 17X-195-282 183-190-274

1Ε4Κ4 1Ε7Β1 1E7C1 1E7F2 1Ε7Η2 1E7J 1Ε7Ν5

1Ε7Ρ1 1Q11G 1Q11J 1Q4 1Q6B2 1Q6C 1Q7A

1Q8A 1Q8C 1Q9B 1Q9D1 1Q9D2 1Q9F1 1Q9F2

1Q9L 200 20Υ 215 220 226 227 22Χ 22Υ 246

247 250 251 253 254 255 25Υ 29Χ 29Υ 30Υ

311 31Υ 323 326 32Υ 332 342 34Υ 351 355 360

361 365 366 367 368 36Υ 371 373 37Υ 3Α12Α4Α

3Α12Β3 3A12C6 3Α13Β6 3A13C10H 3A13C1C

3A13C2B 3A13C9 3Α19Α4 3Α19Β1 3Α19Β2

3Α19Β3 3A19C1 3A19C2 3A19C3 3A19D2 3A19D3

3A7V2A3 3A7V2A4 3A7V2E1 3A7V2J1 3A7V4A3

3A7V4A4 3A7V4E1 3A7V4G1 3A7V4J2 3Α8Α4

3Α8Β2 3A8C4 3A8G1 431 433 436 462 464 490

491 574 584 594 612 614 620 621 623 625 628

62Χ 650 65Χ 661 662 665 668 670 671 675

676 681 698 69Υ 732 771 776 790 79Υ KM ΚΡ KR

LD LS LZ MB ΜΚ ML NC QS QU ZJ

(72) Inventors TSUNG-YING SHEN, GORDON LYN WALFORD

and BRUCE EDWARD WITZEL

(54) SUBSTITUTED SALICYLIC ACIDS AND THEIR DERIVATIVES

(71) We, Merck & Co. Inc., a corporation duly organised and existing

under the laws of the State of New Jersey, United States of America, of Rahway, New Jersey, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:This invention provides compounds of the formula :

in which A is a methylene or carbonyl radical; Υ is a methylene, imino, alkylimino, thio or oxy (-O-) radical, except that Υ is not oxy when each X is hydrogen and A is carbonyl, R₂ is a hydrogen atom or an acyl, alkyl or alkoxycarbonyl radical; R₃ is a hydrogen or halogen atom or an alkyl, cycloalkyl, alkoxy or haloalkyl radical;

each X is a hydrogen or halogen atom or an alkyl, hydroxy, alkoxy, acyloxy, haloalkyl, nitro, amino, alkylamino, dialkylamino, acylamino, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfamoyl, aminosulfinyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, mercaptoalkyl, acylaminomethyl, alkylthioalkyl, cyano, carboxy, alkoxycarbonyl, carbamoyl, aryl, aralkyl, aryloxy, aralkoxy or acyl radical; R, is a hydroxy, amino, alkoxy, alkylamino, dialkylamino, dialkylaminoalkylamino, dialkylaminoalkoxy, hydroxyalkoxy, polyhydroxyalkoxy, alkoxyalkoxy, 5 phenoxy, substituted phenoxy, alkanoylaminoalkoxy, hydrazino, N-morpholmo, piperidino, anilino or hydroxyalkylamino radical or a radical derived from a naturally occurring amino acid radical with attachment at the Ν; and none of the acyclic alkyl, alkoxy, and acyl residues mentioned contains more than six carbon atoms, and pharmaceutically acceptable salts and anhydrides of the acids, i.e. the compounds in which, 10 in the formula, R, is a hydroxy radical.

- Among values of R₂ are formyl, acetyl, propionyl, butyryl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl and hexoxycarbonyl; among values of R₃ are chlorine and fluorine (which are preferred

to bromine and iodine), trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, 15 cyclobutyl, cyclopentyl, cyclopropyl, cyclohexyl, cycloheptyl, methoxy, ethoxy, isopropoxy and butoxy; among values of X are chlorine and fluorine (which are preferred to bromine and iodine), methyl, ethyl, propyl, isopropyl, butyl, pentyl, methoxy, ethoxy, isopropoxy, butoxy, benzoyloxy, acetoxy, propionoxy, trifluoromethyl, methylamino, propylamino, pentylamino, dimethylamino, dibutylamino, propylpentyl- 20 amino, formamido, acetamido, propionamido, butyramido, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, butylsulfinyl, methylsulfonyl, ethylsulfonyl, butylsulfonyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, methylethylaminomethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxyethyl, ethoxypropyl, mercaptomethyl, mercaptcethyl, methylthiomethyl, ethyl- 25 thioethyl, ethylthiopropyl, methoxycarbonyl, ethoxycarbonyl, phenyl, halophenyl, tolyl, salicyl, benzyl, formyl, acetyl and butyryl.

The preferred compounds are those in which 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 five-membered ring above. 30

Compounds of the above formula have been found to possess a high degree of anti-inflammatory activity and therefore to be of value in the treatment of arthritic

and dermatological disorders, such as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic fever, and to possess a useful degree of analgesic, anti-pyretic, diuretic, anti-fibrinolytic and hypo-glycemic activity. 35

For these purposes the compounds of the invention may be administered orally, topically, parenterally or rectally in formulations containing conventional non-toxic pharmaceutically acceptable carrier, adjuvants and vehicles. In addition to the treatment of warm-blooded animals, the compounds of the invention are effective in the treatment of humans, but it is only the treatment of non-human animals by administra- 40 tion to them of an effective amount of a compound of Formula I or a salt or anhydride thereof that forms part of the present invention.

The non-toxic pharmaceutical carriers indicated above include either soh'ds or

liquids. Exemplary of solid carriers are lactose, corn starch, gelatin, talc, sterotex, stearic acid and magnesium stearate. Exemplary of liquid carriers are peanut oil, 45 olive oil, sesame oil and water. Similarly, the carrier or diluent may include a timedelay 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 50 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.

The compounds of Formula I are present in an amount sufficient to give the 55 desired anti-inflammatory or other therapeutic effect. Advantageously, the composi-

tion will contain the active ingredient, in an amount such that from 1 mg to 100 mg

per kg body weight per day (50 mg to 7 g per patient per day), preferably from about 2 mg to 50 mg per kg body weight per day (100 mg to 3 g per patient per day),

can be administered. The most rapid and effective anti-inflammatory effect is obtained 60 from administration, preferably orally, of a daily dosage of from about 4 to 20 mg

per 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 and many other factors that modify the actions of drugs,

for example, age, body weight, sex, diet, time of administration, route of administra- _ . 65 tion, rate of excretion, drug combination, reaction sensitivities and severity of the materials of the formula: particular disease. The compounds of the invention may be produced from starting

and convenient techniques for their preparation are well known. In addition to tire above, a number of processes for the preparation of the phenolic starting materials from available reactants may be presented as follows:

where X, R₂ and R₃ are as defined above.

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

where Υ and R₃ are as defined above, and

X" is hydrogen, alkyl, alkoxy, halogen, haloalkyl, rutro, acylamino, alkylthio, alkylsulfonyl, alkylsulfinyl, acyl, aiyloxy, aryl, aralkyl, carboalkoxy or acylaminomethyl.

The phenol and alcohol are heated with HC1. at 80°C. for six hours and the aqueous layer is separated, acidified and extracted with ether to produce the product.

X" is as defined above

Y^r is O or S

R₂ and R₃ are as defined above.

The preferred compounds are those in which the

group is joined to the 2 or 3 position. When j'oined to the 2-position it is desirable for the 3, 4 or 5-position to contain an Η, halo, or alkyl.

(1) Acylation: To the mixture of the 5-membered ring compound 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 used in the above reaction including the use of catalysts such as A1C1., BF₃, ZnCI₂ and I₂. The acylation may also be accomplished using the acylating acid in phosphoric acid or P₂0₅ 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 ΚΟΗ 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.

R₂ is alkyl

X and R₃ are as defined above.

(1) Acylation: The pyrrole-Grignard mixture is cooled; the acylating agent added;

the mixture acidified; the ethereal layer separated, washed, dried and filtered and the residue distilled or chromatographed.

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

R₂ is alkyl and A, X, Υ and R₃ are as defined above.

Methylene chloride is added to the alkoxy material; boron tribromide is then added at low temperatures; the mixture is stirred and brought to room temperature;

acid is added; the layers are separated; the methylene chloride mixture is dried, filtered, concentrated in vacuo; and the residue is chromatographed on silica gel.

Carboxylation of the starting materials of the formula:

prepared in accordance with section (a), (b), (c), (d) or (℮), proceeds as follows :

where X", Υ, A and R₃ 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 C0₂ atmosphere; heat is applied, the mixture is cooled, added to water and filtered; and 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 (treatment of an alkyl sodium derivative with carbon dioxide), may be used.

In the following examples, which are given for the purpose of illustration of the invention, “m.” means “moles” and temperatures are on the Ctentigrade scale. Examples 1-7 are concerned with preparing starting materials and/or intermediate compounds; Examples 8-26 are concerned with preparing compounds in accordance with the present invention.

5 10 15

20 25 30 Example 1

Preparation of 2{^-anisoyl)-5-fluorothiophenc

A). To a solution of 2-fluorothiophene (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 is stirred at room temperature 5 for three hours, water added carefully, the layers separated, the benzene layer washed well with water, dried and concentrated in vacuo, and the residual material chromatographed on a silica gel column using an ether- and petroleum-ether system (ν/ν 0-80% ether) as eluant to yield 2-(p-anisoyl)-5-fluorothiophene.

Β). When m-methoxybenzoyl chloride, 4-methoxy-2-methylbenzoyl chloride, 2- 10 chIoro-4-methoxybenzoyl chloride, 2-fluoro-4-methoxybenzoyl chloride, 4-methoxy-2-trifluoromethylbenzoyl chloride, 2-methoxy-4-benzyloxybenzoyl chloride, or p-benzyloxybenzoyl chloride is used in place of p-methoxy benzoyl chloride in the above reaction, the corresponding 5-(substituted benzoyl)-2-fluorothiophene is obtained.

C). When 2-chlorothiophene, 2-bromothiophene, thiophene, 2-methylthiophene, 15 2-acetylthiophene, 2-benzylthiophene, 2-phenylthiophene, 2-methylmercaptothiophene, 2-acetamidothiophene, 3-fluorothiophene, (2 and 3)-methylsuIfonylthiophene, 2,5-dimethylthiophene, 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, 2-nitrofuran, 2-trifluoromethylfuran, 2-carbomethoxy- 20 furan, 2-carbomethoxythiophene or 2,5-dichlorothiophene are used in place of 2-fluorothiophene in the above acylations, the corresponding (substituted-benzoyl)-sub-stituted-thiophenes and furan are obtained.

Preparation of a:-(2-phenylcyclopenta-(2,4)-dienyl)-p-cresol 25 To a mixture of 2-phenylcyclopentadienyl sodium (obtained from the parent compound with sodium in ethanol) (0.04 m.) is added />-(chlorometfayl)-phenol (0.04

m.) during one hour at 25°C. and the resulting mixture stirred for 5 hours. The ethanol is removed in vacuo, the residue extracted with chloroform and the chloroform extract dried, filtered and concentrated in vacua to yield «-(2-pbenylcyclopenta- 30 (2,4)-dienyl)-p-cresol.

When a substituted cyclopentadienyl sodium is used in the above reaction in

place of the 2-phenylcyclopentadienyl sodium, the corresponding substituted «-(cycIo-penta-(2,4)-dienyl)-p-cresols are obtained. Representative members of this class inelude: 2-fluorocyclopentadienyl, 3-methylcycIopentadienyl and 3-ethoxycyclopentadi- 35 enyl sodium.

Preparation of 2-(p-methoxybenzoyl)-l-methylpyrrole

N-methylpyrrole (21 g.) is added dropwise to an ethereal-Grignard mixture pre-

pared from magnesium (6.2 g.) and ethyl bromide (31 g.). When evolution of ethane 40 has ceased, the pyrrole-Grignard mixture is ice-cooled, and p-methoxybenzoyl chloride

(36.3 g.) added dropwise; after the addition the mixture is stirred at ambient temperatures, ice water is added cautiously, the aqueous mixture is acidified with sulfuric

acid and the ethereal layer is separated and washed with dilute sulfuric acid and water

until the washes remain neutral. The ethereal solution is dried and filtered and the 45 residue distilled under reduced pressure to yield 2-(p-methoxybenzoyl)-l-methylpyr-

role.

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-(ρ-benzyloxybenzoyl)-l-methvlpyrrole is obtained. 50 In addition to N-methylpyrrole, the above procedure is applicable to pyrroles in

which other alkyl radicals, such as ethyl and butyl, are attached to the nitrogen atom.

Furthermore, substituted pyrroles in which the substituent represents the radical

X, as defined above, are contemplated in the acylation reaction set forth above. Accordingly, a pyrrole-Grignard mixture in which the pyrrole is, for example, Ν- 55 ethyl 2-fluoropyrrole N-methyl 2-phenylpyrrole or N-methyl-2-methylpyrrole will re-

sult in the production of the corresponding acylated material.

Preparation of p-(5-fluorofurfuryl)-phenol

A mixture of phenol (0.1 m.), 5-fluorofurfuryl alcohol (0.1 m.), and IN hydro- 60 chloric acid (0.15 ml.) is heated at 80° for 6 hours, the mixture is distributed be-

tween ether and dilute aqueous sodium hydroxide solution, the aqueous layer is separated, acidified and extracted well with ether and the ethereal extracts are fractionally distilled to yield p-(5-fluorofurfuryl)-phenol.

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

For example, when resorcinol monomethyl ether, wz-cresol, meta-fiuorophenol or meta-chlorophenol is used in place of phenol, the corresponding substituted compound is obtained. For example, meta-fiuorophenol will result in p-(5-fluorofurfuryl) mfluorophenol.

In addition to the use of substituted furfuryl alcohols other than the 5-fluoro illustrated above, the reaction is applicable for the preparation of phenols using the various thiophenes and pyrroles contemplated by the invention.

Preparation of 2-fluoro-5-(p-methoxybenzyl)-thiophene

A mixture of 2-fluoro-5-(p-methoxybenzoyl)-thiophene (0.1 m.) 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.), then potassium hydroxide pellets (0.2 m.), added, and the mixture is heated until gas evolution ceases. On cooling, the mixture is added to water (300 ml.) and extracted with benzene. The benzene extracts are washed well with water, dried and concentrated in vacuo, and the residual material is distilled under reduced pressure or chromatographed [silica gel column; ether-and-petroleum-ether system (ν/ν 0-80% ether)] to yield 2-fluoro-5-(p-methoxybenzyl)-thiophene.

It may be noted that reduction may also be carried out by the well known Clemmensen procedure using 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 correspond-ingly-substituted benzyl thiophenes, furans and pyrroles are obtained.

For example, reduction of 5-chloro-2-(m-methoxybenzoyl)-thio/jhene; 2,4,5-trimethyl 3 - (2 - chloro - 4 - methoxybenzoyl) - furan and 3-(p-methoxybenzoyl)-lmethylpyrrole in accordance with the above process results in the production of 5-chloro - 2 - (τη - methoxybenzyl)thiophene; 2,4,5 - trimethyl - 3 - (2 - chloro - 4-methoxybenzyl)furan and 2 - (ρ - methoxybenzyl) - 1 - methylpyrrole respectively.

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

Preparation of p-(5-fluorothenoyl)-phenol

A mixture of 2-(p-benzyIoxybenzoy])-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 vacua to yield p-(5-fluorothenoyl)phenol.

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

Preparation of 2-fluoro-5-(p-hydroxybenzoyl)-thiophene

To a cold (-60°) mixture of 2-fluoro-5-(p~methoxybenzoyl)-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 is allowed to warm slowly to room temperature. After stirring for several hours, a minimum of 10% aqueous sodium hydroxide is added to hydrolyse the complex. The mixture is then acidified with 2% hydrochloric acid and the layers separated. The methylenechloride mixture is dried, filtered and concentrated in vacuo, and the residue chromatographed on silica gel using an ether-and-petroleum-ether system as eluant to yield 2-fluoro-5-(p-hydroxybenzoyl)-thiophene.

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

Preparation of 5-(5^/-fluoro-2'-thenoyl)-salicyIic acid

An intimately ground mixture of 2-fluoro-5-(p-hydroxybenzoyl)-thiophene (5 g.) and anhydrous potassium carbonate (15 g.) is heated at 200°C. in a 1200ΐ-1400 p.s,i, carbon dioxide atmosphere for 8 hours. The mixture is cooled, added to water 5 10 15 20 25 30 35 40 45 50 55 60 (300 ml.), allowed to stir, filtered, and tie filtrate acidified with dilute hydrochloric acid to yield 5-(5'-fluoro-2'-thenoyl)-salicylic add.

Purification may be effected 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 5 corresponding salicylic acid is obtained.

A representative list of salicylic adds are as follows:

5-(5-phenyl-2-cycIopenta(2,4)dienylmethyl)-salicylic add 5-(5-fluoro-2-cydopenta(2,4)dienylmethyl)-salicylic acid 5-(5-nitro-2-cyclopenta(2,4)dienylmethyI)-saIicylic add 5-(5-acetyl-2-furoyl)-salicylic add

5-(5-cyclobutyl-2-furylmethyl)-salicylic acid

4-(5-ethyl-2-thienylmethyl)-saIicylic acid

4- (5-nitro-2-thenoyl)-salicylic add

5-(5-methylmercapto-3-thenoyI)-salicylic add

5- (5-fluoro-2-thienylmethyl)-salicylic acid 5-(5-triflnoromethyl-2-N-methylpyrrylmethyl)-salicyIic acid

2-(3'-carboxy 4'-hydroxybenzoyl)-5-fluoro N-methylpyrrole.

Preparation of methyl 5-(5'-cyano-2'-thenoyl)salicylate

A mixture of methyl 5-(5^,'-bromo-2'-thenoyl)-salicylate (0.02 m.), cuprotis cyanide

(0.03 m.), and N-methylpyrrolidone is de-aerated, covered with a nitrogen atmosphere

and heated slowly to 180°C. The mixture is kept at this temperature for 3 hrs., allowed to cool and partitioned between benzene and 7% hydrochloric acid contain-

ing ferric chloride (0.03 m.). The benzene layer is then separated, dried and concentrated and the residue chromatographed on a silica gd column using an ether-and-petroleum-ether system as eluant (ν/ν 5-80% ether) to yield methyl 5-(5'-cyano-2^fthenoyl)salicylate.

Example 10

Preparation of methyl 2-acetoxy-5(5^,-bromcHnethyl-2^/-thenoyl)-benzoate

A mixture of methyl 2-acetoxy-5(5^,-methyl-2^,-thenoyl) benzoate (0.05 m.), Νbromosuccinimide (0.05 m.), carbon tetrachloride (500 ml.) and dibenzoyl peroxide (0.002 m.) is refluxed gently for 3 hrs and cooled. The sucdnimide is removed by filtration and the solvent removed in νααω to yield methyl 2-acetoxy-5(5'-bromomethyl-2'-thenoyl)benzoate.

Example 11

Preparation of methyl 5-(5^,-hydroxymethyl-2^,-thenoyl)salicylate

A mixture of methyl 2-acetoxy-5(5'-bromomethyl-2^f-thenoyl)benzoate (0.01 m.),

silver acetate (0.01 m.) and acetic add (30 ml.) is heated gently for three hours, cooled and filtered, and the filtrate concentrated in vacuo to a residue of crude methyl 2-acetoxy-5-(5'-acetoxymethylthenoyl)-benzoate. Anhydrous methanol (50 ml.) and /Mnluenesulfonic add (0.3 g.) are added and the mixture is refluxed for three hours, concentrated and distributed between water and chloroform. The chloroform layer

is dried and concentrated, and the contents chromatographed on a silica gel column using an ether-and-petroleum-ether system (ν/ν 0-100% ether) as eluant yielding methyl 5-(5'-hydroxymethyl-2'-thenoyl)saIicyIate.

When potassium thiolacetate is used in place of silver acetate in the above re-

action, methyl 5-(5'-mercaptomethyl-2'-thenoyl)salicylate is obtained.

Example 12

Preparation of methyl 5-(5'-methoxymethyl-2^,-thenoyl)saIiqrlate

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 mix-

ture is refluxed gently for one hour and cooled, dilute hydrochloric acid is added

to neutralize the mixture and the solvents are removed in vacuo. The residue is chromatographed on a silica gel column using an ether-and-petroleum-ether system (ν/ν 0-40% ether) as eluant to yield methyl 5-(5'-methoxymethyl-2'-thenoyl)-salicylate.

When potassium methylthiolate is used in place of sodium methoxide, methyl 5-(5'-methylthiomethyl-2'-£henoyl)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 removal in vacua and the residue taken up in 2.5 Ν hydrochloric acid, filtered, basified, and the resultant methyl 5-ζ5^-11-methylaminomethyl-2^/-thenoyl)salicylate collected.

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

Example 14

Preparation of 2-acetoxy-5-(5^,-chloro-2^,-thenoyl)-benzoic add

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-m.l. portion of water. The aqueous system is then extracted well with chloroform and the chloroform extracts are washed with IN hydrochloric acid and 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 pr-opionoxy or butyroxy compound is obtained.

Example 15

Preparation of methyl 2-carboxy-4-(5'-fluorofurfuryl)-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 m.) over one hour with constant shaking and cooling. When the odour of the chlorocarbonate is essentially absent, hydrochloric acid (IN, 100 ml.) is added and the mixture filtered. The benzene layer is then separated, dried and filtered, and the solvent is removed in vacua to yield methyl 2-carboxy-4-(5^!'-fluorofurfuryl)-phenyl carbonate.

Example 16

Preparation of 2(3'-carboxy-4^,-methoxybenzyl)-5-fluorothiophene

To a mixture of 2(3'-carboxy-4'-bydroxybenzyl)-5-fluorothiophene (0.01 m.) in 2Ν sodium hydroxide solution at 90°C. is added dimethyl sulfate (0.10 m.) in small portions over ten hours, the mixture being kept basic throughout the addition. Water is added, the mixture filtered, the filtrate acidified and 2(3^f-carboxy-4'-methoxybenzyl)-5-fluorothiophene 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 Μ sodium methoxide in absolute methanol is heated for 30 mins, at ca. SO⁰ in a stoppered bottle, the excess of methanol removed in vacuo, dilute hydrochloric acid added and the mixture extracted with chloroform. Concentration of the chloroform solution yields methyl 5-(5^f-methoxyfuroyl)-salicylate.

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

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

When the 5-bromo compound is reacted with an excess of methanolic dimethylamine, the 5-dimethylamino analogue is obtained.

Example 18

Preparation of methyl 5-(5'-carbamyl-2-thenoyI)-salicylate

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

Example 19

Pjsparation of d-fS'-carboxy^'-thenoy^-salicylic add

To a mixture of 5-(5'^,-carbomethcExy-2’^,-thenoyl)salicylic acid (0.01 m.) and 5 !0 15 20 25 30 35 40 45 50 55 methanol (ICO 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 jml.) and filtered and the filtrate is acidified with 2.5 Ν hydrochloric acid. The 5-(5'-carboxy-2'-thenoyl)-saIicylic 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 using a diazomethane reagent. Further exemplification of esterification procedures is indicated in the following examples:

Example 20 A

' Preparation of methyl 5(5⁷-fluoro-2'-thenoyl)-saIicylate 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 and 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.

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(5'-fluoro-2'thenoyl)-salicylic acid in the above example, the corresponding esters are obtained.

Example 20 Β

Preparation of methyl 2-acetoxy-5-(5^,-fluoro-2'-thenoyl)-benzoic acid Diazomethane in methylene chloride is added to an ice-cooled mixture of 2-acetoxy-5-(5^,-fluoro-2'-thenoyl)-benzoic add in methylene chloride until nitrogen evolution ceases and the colour of diazomethane persists. The solvent is then removed in vacuo to yield methyl 2-acetoxy-5-(5'-fluoro-2'-thenoyl)-benzoate.

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

Example 21

Preparation of phenyl 5(5'-fluoro-2'-furfuryl)saIicyIate

To a mixture of polyphosphate esters (Ρ.Ρ.Ε.) (15 equiv.) in chloroform is added one equivalent each of 5(5'^,-fluoro-2'-furfuryl)salicylic acid and phenol, and the resultant mixture is heated gently for 30 minutes. The chloroform mixture is cooled, washed with dilute bicarbonate solution, dried, filtered and evaporated in vacuo to yield phenyl 5(5'-fluoro-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)saIicylaniIide

A mixture of phenyl 5(5'-nitro-2''-furfuryl)salicylate (0.1 m.), aniline (0.1 m.), and 1-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 is added. The mixture is heated for 10 min., filtered hot, and cooled. The collected anilide is then recrystallized yielding pure 5-(5'-nitro-2'-furfuryl)salicyIanilide.

Example 23

Preparation of 5-(5⁷-fluoro-N-methylpyrrylmethyl)salicyIainide

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 and piperidine are used in place of ammonium hydroxide, the corresponding amides are obtained.

Example 24

Preparation of N,N-diethylaminoethyl 5-(5'-phenyI-2'-cydopenta(2,4) dienylmethyl)salicylate

To a mixture of 5-(5''-phenyl-2^,-cyclopenta(2,4)dienylmethyl)salicylic acid (0.01 m.) and N,N-diethylethanolamine (0.01 m.) in anhydrous tetrahydrofuran (100 ml.) 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 vacua and the residue partitioned between ether and IN hydrochloric acid. The layers are separated and the aqueous layer washed once with fresh ether and neutralized with saturated sodium bicarbonate solution. Extraction with chloroform, followed 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)salicylate.

Example 25

Preparation of sodium 5-(5'-methyl-2'-thienylmethyl)salicylate

Solutions of 5-(5'-methyl-2'-thienybnethyl)salicylic acid in methanol and sodium hydroxide (1 equiv.) in water are mixed, heated for solution and filtered, and the filtrate is concentrated in vacua 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 disodium and dipotassium salts are obtained.

Example 26

Preparation of diethylaminoethanol salt of 5-(5 '-chIoro-2^r-furfuryl)salicylic

acid

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

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