CS199283B2 - Method of preparing aryloxyalkyl aminobenzoic acids and esters thereof - Google Patents

Description

The invention relates to novel aryloxyalkylaminobenzoic acids and their esters and to a process for their preparation. They are useful as synthetic hypolipidemic compounds which are useful in the treatment of artheriosclerosis as they lower serum cholesterol, triglycerides and phospholipids. The compounds of the invention can be used to lower serum lipid levels without disrupting the later stages of cholesterol biosynthesis. These are new substances in terms of chemical construction and possibly in terms of their effect.

The present invention provides a process for the preparation of aryloxyalkylaminobenzoic acids and their esters of formula

X- Y- O- Co _I wherein R ₁ represents

Y is a branched or straight alkylene chain of formula

C 1 Hvn, where n is 2 to 12,

R 1 is hydrogen, C 1 -C 4 alkyl or 2,3-dihydroxypropyl,

X phenyl-, naphthyl-, thienyl-, furyl-, 1,2,3,4-tetrahydronaphthyl-, 4-chloro-1-naphthyl and substituted phenyl, wherein the phenyl contains halogen, hydroxy-, C1-C4 alkoxy- , C 1 -C 4 alkyl-, cyano-, trihalomethyl-, amino-, C 1 -C 4 alkanoylamino-, C 1 -C 4 alkylamino-, di-C 1 -C 4 alkylamino-, phenoxy-, p-chlorophenoxy-, benzyloxy-, p- -chlorobenzyloxy- or C 2 -C 6 cycloalkyl, and when R 1 is hydrogen, their alkali metal or organic base salts thereof, characterized in that the p-aminobenzoic acid derivative of the general formula

199263 wherein R 1 is as defined above, is reacted with an alkylating agent capable of introducing the group X-O-Y-, wherein X and Y are as defined above, at a temperature of 50-170 ° C for 1-25 hours.

Suitable C1-C4 alkyl groups include, for example, methyl, ethyl, isopropyl, propyl, tert-amyl, n-hexyl and tert-butyl.

In the following description, the term "lower" alkyl, alkoxy and the like means in each case a corresponding group having 1 to 4 carbon atoms.

The novel compounds of the invention are colorless or light brown crystalline solids or colorless or light brown oils. They are usually soluble in organic solvents such as benzene, chloroform, dichloromethane, N, N-dimethylformamide, dimethylsulfoxide and lower alkanols.

The compounds of the invention are bases and can be converted into their non-toxic acid addition salts such as sulfuric, hydrochloric, phosphoric, succinic, citric, and the like. Compounds in which R 1 is hydrogen can be reacted with bases such as sodium hydroxide, potassium hydroxide and the like, or with organic bases such as ammonium hydroxide, pyridine, mono-, di- or tris-lower alkylamines, such as methylamine, diethylamine, trimethylamine, dibutylamine and the like, to form the corresponding carboxylic acid salts.

Suitable solvents for the alkylations are hexamethylphosphoramide, N, N-dimethylformamide, Ν, Ν-dimethylacetamide, lower alkanols, chloroform, dimethylsulfoxide, benzene, xylene, acetonitrile and the like.

Alkylations can be carried out with an equivalent of a base such as an alkali metal carbonate or bicarbonate. Alternatively, by reaction of lower alkyl p-aminobenzoates, p- [aryloxyalkyl] aminobenzoates can be prepared by reacting lower alkyl p-aminobenzoates with aryloxyalkyl halide in the presence of sodium hydride equivalent in inert solvents such as hexamethylphosphoramide, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, xy and the like at 50 to 170 ^° C for 1 to 25 hours.

In the case of aryloxyalkyl chlorides, alkylation of lower alkyl p-aminobenzoates can be performed with sodium or potassium iodide equivalent in inert solvents such as hexamethylphosphoramide, Ν, Ν-dimethylformamide, Ν, dim-dimethylacetamide and the like.

The p- (aryloxyalkyl) aminobenzoic acids of the invention are prepared by hydrolyzing the corresponding esters by reaction with alkali metal hydroxides such as sodium hydroxide or potassium hydroxide in a lower alkanol at a temperature of 25 to 100 ° C. Alternatively, p- (aryloxyalkyl) aminobenzoic acids can be prepared by hydrolyzing p- (aryloxyalkyl) aminobenzoates with mineral acids such as hydrochloric, hydrobromic or sulfuric acid in water or aqueous alkanols.

Esters of p- (aryloxyalkyl) aminobenzoic acids can be prepared by converting the corresponding acids to acid chlorides using reagents such as thionyl chloride and oxalyl chloride and reacting the intermediate acid chlorides with lower alkanols, lower-alkylaminoethanols, lower alkoxyethanols and the like. Alternatively, metal salts such as sodium, potassium, zinc salts and the like of carboxylic acids, reacted with lower alkyl halides and substituted propyl halides such as 3-halo-1,2-propanediol and the like in solvents such as hexamethylphosphoramide or Ν, Ν-dimethylformamide to form esters p- (aryloxyalkyl) aminobenzoic acids of the formula I.

The novel p- (aryloxyalkyl) aminobenzoates of the invention can be prepared by reductive alkylation of lower alkyl p-aminobenzoates or p-aminobenzoic acid with a suitable aryloxyalkylaldehyde or ketone in the presence of a noble metal and / or nickel or cobalt or suitable metal hydride catalyst. For example, Raney nickel, hydrogen and aryloxyalkylaldehyde may be used in the .beta.-aminobenzoate, such as aluminum chloride, piperidinium acetate or acids in reductive alkylation.

An alternative method of preparation is to reduce the 4- (acylamino) benzoic acid ester or the corresponding acid with a metal hydride. Reduction of ethyl 4-hexadecanoylaminobenzoate or 4-hexadecanoylaminobenzoic acid with diborane at room temperature or above for 1 to 6 hours affords ethyl 4-hexadecylaminobenzoate or 4-hexadecylaminobenzoic acid.

These novel aryloxyalkylaminobenzoic acids and esters are prepared by reacting lower alkyl p-aziridinobenzoate, lower alkyl p-haloalkyleneaminobenzoate or lower alkyl 1-p-alkyl 1 (or aryl) sulfonyloxyalkyleneaminobenzoate and aryl-OH type compounds under alkaline or acidic conditions.

Some of the alkylating agents for preparing the novel compounds of the invention may be prepared according to the following scheme:

Ri Ri

XOH + w - C (CH ₂ ) _n CO ₂ R - XO - C (CH ₂ ) _n CO ₂ R

R2 R2 (1) (2) (2)

Κ1

AND

XO-C (CH ₂ ) _n CH ₂ Z

AND

Rz [5] i

Ri

XO-C (CH 2) n CH ₂ OH

Rz (4)

These are cases where it represents

W halogen, n number 0 or 1 to 11,

R 1 is hydrogen or lower alkyl;

R 1 and R 2 are hydrogen atoms or lower alkyl groups.

Reduction of the intermediate aryloxyalkyl derivative 3 yields the corresponding alcohol 4, which is converted to the desired alkylating agent 5 (wherein Z represents a halogen, O-umthanesulfonate residue and the like).

the compounds of the invention have a hypolipidemic effect. The mechanism of action of these compounds is not known, and the invention is not limited by any mechanism. However, it was confirmed that the compounds of the invention have a hypolipidemic effect, animal experiments, which were carried out as follows:

Compounds were administered orally, admixed with food, to groups of 4 to 6 male CFE rats (Carworth Farms), control groups of 6 to 8 rats were fed only, and test groups were fed a mixture with the specified weight part of the compound. in the assay, sterol concentration was determined by the extraction method of H. H.effeff, Amer. J. Clin. Path., 31, 310 (1959) and by colorimetric determination according to Zlatkis et al., J. Lab. Clin. Med., 44, 486 (1953). Serum triglycerides were determined by the automated procedure of Kessler and Lederer ("Automation in Analytical Quenders", Skeggs, LT, (Ed.), Mediad, Inc., New York, 1965, p. 341J). hypolipidemically effective when lowering serum sterol levels below that found in the control group and / or when lowering triglyceride levels below those found in the control group. and the degree to which these compounds reduce sterol and triglyceride levels after one week of dosing.

Table 1

Compound % of the compound in the diet % reduction of t sterol serum triglycerides p - [(2-phenoxyethyl) amino] benzoic acid 0.1 22nd 41 ethyl 1 - [(2-phenoxyethyl) amino] benzoate 0.1 21 41 p - [(3-phenoxy propyl) amino] benzoic acid 0.1 16 31 ethyl p - [(3-phenoxypropyl) amino] benzoate 0.1 10 27 Mar: p - [(4-phenoxy butyl) amino] benzoic acid 0.1 4 53 ethyl p - [(6-phenoxyhexyl) amino) benzoate 0.05 19 Dec 15 Dec p-j [2- (p-bromophenoxy) ethyl] aminobenzoic acid 0.1 10 47 p - [(11-phenoxyundecyl) amino] benzoic acid 0.1 7 41 p - [[2- (2-naphthyloxy) ethyl) amino) benzoic acid 0.1 13 47 ethyl p [2- (2-naphthyloxy) ethyl) aminobenzoate 0.1 10 43 p - [(2-phenoxypropyl) amino] benzoic acid 0.05 24 52 p- [2- (1-naphthyloxy) ethyl] aminobenzoic acid 0.1 17 42

acid

The compounds of the invention are useful as hypolipidemic agents in mammals when administered in an amount ranging from about 0.5 mg / about to 40 mg / kg of body weight per day. A preferred dosage regimen for optimal results is from about 2 mg / kg to about 29 mg / kg of body weight per day. The daily dose used for a patient weighing about 70 kg is about 35 mg to about 2.8 g, preferably about 140 mg to about 2.0 g.

The active compounds of the invention may be administered orally, for example with an inert diluent or with an assimilable edible carrier, or encapsulated in hard or soft gelatin capsules, or compressed into tablets, or mixed directly with the food ingredient. For oral therapeutic administration, the active ingredients of the invention may be mixed with the excipients and may be used in the form of tablets, powders, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. However, the percentage in the compositions may vary and may conveniently be from about 5 to about 75% by weight or more, based on the dosage unit. The amount of active compound in such therapeutically useful preparations should be such that a suitable dosage will be obtained. Preferably, oral preparations are prepared so that the unit dosage form contains about 10 to about 500 mg of the active compound.

Tablets, powders, pills, capsules and the like may also contain the following: a binder such as tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrating agents such as corn starch, potato starch, alginic acid and the like lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose or saccharin, and flavors. When the unit dosage form is a capsule, the formulation may contain, in addition to substances of the above type, a liquid carrier such as a fatty oil. Various other substances may be present, such as coating agents and modifiers of the otherwise physical form of the dosage units. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. The syrup or elixir may contain the active compounds, sucrose as a sweetener, methyl and propylparabens as preservatives, a colorant and a flavoring such as cherry or orange flavor. Any agent used in the preparation of all such unit forms should be pharmaceutically pure and substantially non-toxic in the amounts used.

The active ingredients may also be formulated as sustained release formulations.

Example 1

6- (2-naphthyloxy) -1-hexanol

4.2 g of 57% sodium hydride in oil, 50 ml of hexamethylphosphoramide and 15.8 g of 2-naphthol are added to a cooled round-bottomed flask. After 22 hours the mixture was allowed to warm to room temperature and 13.6 g of 6-chloro-1-hexanol was added. The mixture was heated at 110 ° C overnight, cooled, diluted with water and extracted with ether. The ether extract was diluted with sodium hydroxide solution, then water, dried over magnesium sulfate and the solvent removed in vacuo. The solid was dissolved in ether and washed with sodium hydroxide solution. The ether layer was dried over magnesium sulfate and the solvent was removed in vacuo. 15.9 g of product are obtained in the form of crystals, m.p. 53-56 ° C.

Example 2

6- (2-naphthyloxy) -1-hexanol-O-methylsulfonate

To a mixture of 10.4 g of 6- (2-naphthyloxy) -1-hexanol and 8.1 g of triethylamine in 250 ml of dichloromethane cooled to -8 ^° C was added dropwise 5.1 g of methanesulfonyl chloride under nitrogen. After 1 hour at 0 to -8 ° C, the mixture was washed with cold water, 10% hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed in vacuo. Obtained as a white solid.

Example 3

Ethyl 1-p - {[6- (2-naphthyloxy) hexyl] aminobenzoate

A solution of 10.0 g of 6- (2-naphthyloxy-1-hexanol-amethanesulfonate) and 9.7 g of ethyl 4-aminobenzoate in 50 ml of hexamethylphosphoramide was heated at 110 ° C for 16 hours, cooled, diluted with water, filtered and solid. The product was washed with ethanol and water to give 7.7 g of product, and recrystallized from ethanol and one of the acetone-hexane mixtures to give crystals of m.p. 109-110 ^° C.

Example 4 p-f [6 (2-naphthyloxy) hexyl] aminobenzoic acid

A solution of 4.8 g of ethyl p - {[6- (2-naphthyloxy) hexyl jaminoibenzoate] and 4.8 g of potassium hydroxide in 100 ml of 95% ethanol is refluxed for 3 hours. The solution was cooled, diluted with water and acidified with concentrated hydrochloric acid. The mixture was filtered and the solid was washed with a mixture of ethanol and water and recrystallized from ether-methylene chloride and acetone. Crystals of m.p. 157-159 ° ^{C are obtained} .

Example 5

2- [2-naphthyloxy) ethanol

A solution of 14.4 g of 2-naphthol, 12.1 g of 2-bromoethanol and 5.9 g of sodium methoxide in 100 ml of ethanol is allowed to stand at room temperature for 2 days. The solvent was removed in vacuo and the residue was extracted with ether. The ethereal extract was washed with water, dried over magnesium sulfate and the solvent was evaporated in vacuo. Crystals of m.p. 65-70 ° C are obtained.

Example 6

2- (2-naphthyloxy) ethanol-O-inethanesulfonate

In the manner described in Example 2, 13.5 g of 2- (2-naphthyloxyethanol in 400 ml of dichloromethane) was reacted with 9.5 g of methanesulfonyl chloride in the presence of 11.4 g of triethylamine to give the product as pale brown crystals.

Example 7

Ethyl 1 -? - [2- [2-naphthyloxy) ethyl] aminobenzoate

A mixture of 18.7 g of 2- (2-naphthyloxy) ethanol-O-methanesulfonate and 23.6 g of ethyl p-aminobenzoate is heated in 300 ml of hexamethylphosphoramide at 110 for 16 hours. The mixture was cooled, diluted with water and worked up as described in Example 3. A crystalline product was obtained. Recrystallization from ethanol gave crystals of m.p. 158-162 ° C.

Example 8

2- (2-thienyl Jetanol-O-methylsulfonate)

A mixture of 2- (2-thienyl) ethanol (12.8 g) and triethylamine (20.2 g) in dichloromethane (500 ml) was treated with methanesulfonyl chloride (12.6 g) as described in Example 2. The product was obtained as an oil.

Example 1 a d 9

Ethyl 1- [2- (2-ethenyl) ethylamino] benzoate

A mixture of 33.0 g of ethyl p-aminobenzoate and 2- (2-thienyl) ethanol-O-methanesulfonate in 100 ml of hexamethylphosphoramide was heated at 125 ° C for 16 hours. The solution was cooled, diluted with water and extracted with ether. The ether extracts were dried (MgSO4) and the solvent removed in vacuo. The residual oil is chromatographed on silica gel (chloroform). The solvent was removed from the product-containing fractions. Crystals are obtained which are recrystallized from hexane. The crystals obtained have a melting point of 93-96 ° C.

Example p-12- (2-thienyl) ethylamino] benzoic acid

A mixture of 29.7 g of ethyl 1- [2- (2-thienylethylamino) benzoate and 29 g of potassium hydroxide in 200 ml of 95% ethanol was refluxed for 3 hours. mp 161-163 ^° C.

Example 11

2- (1-naphthyloxy) ethanol-O-methanesulfonate

To a solution of 18.8 g of 2- (1-naphthyloxy) ethanol and 15.1 g of triethylamine in 425 ml of dichloromethane was added 12.6 g of methanesulfonyl chloride and after working up as in Example 1 the product was obtained.

Example 12

Ethyl p- [2- (1-naphthyloxy) ethyl] aminobenzoate

A solution of 29.1 g of 2- (1-naphthyloxy) ethanol-O-methanesulfonate and 33 g of ethyl p-aminobenzoate in 100 ml of hexamethylphosphoramide was heated at 100 ° C for 16 hours. The solution was treated as described in Example 3 to give the product. Recrystallization gave crystals of m.p. 124-127 ° C.

Example 13 p - ([2- (1-naphthyloxy) ethyl] aminobenzoic acid)

A solution of 12 g of ethyl p- [2- (1-naphthyloxy-ethylamino) -benzoate and 15.8 g of potassium hydroxide in 100 ml of 95% ethanol is refluxed for 3 hours, diluted with 75 ml of water and acidified with concentrated hydrochloric acid. , washed with 50% ethanol and water. Recrystallization from ethanol gives the product as crystals, mp 193-194 ^C C.

Example 14

Ethyl p-J [2- (2,4-dichlorophenoxy) ethyl] aminobenzoate

A solution of 22.8 g of 4-bromo-2,4-dichlorophenetol and 29.8 g of ethyl 4-aminobenzoate in 100 ml of hexamethylphosphoramide is heated to 125 ^DEG C. for 16 hours. The solution is cooled, diluted with 80 ml of water and filtered. The solid was washed with 50% ethanol to give the product. Recrystallization from ethanol gives crystals of m.p. 111-113 ° C.

Example 15 p - [[2- (2,4-dichlorophenoxy) ethyl] amino) benzoic acid

A solution of 15 g of ethyl p- [2- (2,4-dichlorophenoxy) ethyl] aminobenzoate and 15 g of potassium hydroxide in 200 ml of 95% ethanol is refluxed for 3 hours. The solution was cooled, diluted with water, acidified with concentrated hydrochloric acid and filtered. The solid was recrystallized from ethanol. Crystals of m.p. 203-205 ° C are obtained.

Example 16

6- (phenoxy) -1-hexanol

4.2 g of 57% sodium hydride in oil are added to a solution of 10.3 g of phenol in 25 ml of hexamethylphosphoramide. When the evolution of hydrogen ceased, a mixture of 13.6 g of 6-chloro-hexan-1-ol in 25 ml of hexamethylphosphoramide was added and the mixture was heated at 110 ° C for 16 hours. The solution was cooled, diluted with water and extracted with ether. The ethereal extracts were washed with sodium hydroxide solution, dried over magnesium sulfate and the solvent was evaporated in vacuo. White crystals of m.p. 69-74 ° C are obtained.

Example 17

6- (phenoxy) -1-hexanol-O-methanesulfonate

To a mixture of 9.7 g of 6- (phenoxy) -1-hexanol in 250 mL of dichloromethane containing 11.1 g of triethylamine cooled to-2 ° C was added methanesulfonyl chloride (6.95 g). The product was isolated as described in Example 2. The product was obtained as an oil.

Example 18

Ethyl p- (6-phenoxyhexylamino) benzoate

A solution of 13.6 g of 6- (phenoxy) -1-hexanol-O-methanesulfonate and 16.5 g of ethyl p-aminobenzoate in 75 ml of hexamethylphosphoramide is heated at 110 ^° C for 16 hours. The product is isolated as described in Example 3. The crystals obtained are recrystallized from ethanol. The crystals obtained have a melting point of 105-108 ° C.

Example 19 p- (6-Phenoxyhexylamino) benzoic acid

A mixture of 5 g of ethyl p- [6- (phenoxyhexyl) amino] benzoate and 5 g of potassium hydroxide in 100 ml of 95% ethanol is refluxed for 3 hours. The mixture was cooled, acidified with concentrated hydrochloric acid, diluted with water and filtered. The solid was washed with water and 50% ethanol. The crystals obtained melted at 168-170 ° C.

Example 20

11-Phenoxyundecanoic acid

10.5 g of sodium methoxide are added to a mixture of 9.4 g of phenol, 26.5 g of 11-bromodecanoic acid and 250 ml of hexamethylphosphoramide, cooled in an ice bath. A viscous mass was formed and the mixture was stirred and heated to 100 ° C for 20 hours. The mixture was diluted with cold water, acidified with concentrated hydrochloric acid, filtered and the solid washed with water. Gray crystals are obtained. Recrystallization from acetone gives pale gray crystals, mp 76-78 ^C. C. From the mother liquors gave additional crystals, mp 75-77 ^C.

Example 21

11-Phenoxy-1-undecanol

To 100 ml of 1M diborane in tetrahydrofuran, under nitrogen cooled in an ice bath, was added dropwise 13.92 g of 11-phenoxyundecanoic acid in 50 ml of tetrahydrofuran over 30 minutes. The solution was allowed to stand for 19 hours at room temperature and then poured onto ice. The mixture was allowed to stand, then filtered and the solid washed with water. White crystals, mp 56-58 ^C C. Recrystallization of a sample from ethanol gives white crystals, melting at 56.6 to 57.5 ° C.

Example 22

11-Phenoxy-1-undecanol-O-methanesulfonate

To a solution of 10.6 g of 11-phenoxy-1-undecanol, 200 ml of dichloromethane and 8.4 g of triethylamine, cooled to -8 ° C in an ice-salt bath, was added dropwise a solution of 3.38 ml of methanesulfonyl chloride in 10 ml. ml of dichloromethane. The solution was stirred at -8 ° C for 30 minutes, washed with 150 ml of ice water, 75 ml of cold 100% hydrochloric acid, 75 ml of cold saturated sodium bicarbonate, 75 ml of cold saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was removed in vacuo. Obtained off-white crystals, m.p. 54-58 ^° C.

Example 23

Ethyl p - [(11-phenoxyundecyl) amino] benzoate

A mixture of 16.5 g of ethyl p-aminobenzoate, 10.3 g of 11-phenoxy-1-undecanol-O-methanesulfonate and 50 ml of hexamethylphosphoramide is heated at 100 to 110 ° C for 20 hours, then cooled and diluted with 30 ml of ethanol and 10 ml water. After cooling, the solid is filtered off and washed with ethanol-water. (1: 1) and water gave yellow crystals of m.p. 83-87 ° C. Recrystallization from ethanol gave yellow needles, mp 89-90 ^° C.

EXAMPLE 24 p - (4-Phenoxybutylamino) benzoic acid

To a mixture of 15 ml of hexamethylphosphoramide, 0.86 g of sodium hydride (56% in oil) and 4.32 g of 1,4-dibromobutane, cooled in an ice bath, 1.88 g of phenol in 15 ml of hexamethylphosphoramide are added dropwise over 1 hour. The mixture was stirred at 0 ° C for 1 hour ^. = C, 3.30 g of ethyl p-aminobenzoate is added and the mixture is heated on a steam bath for 16 hours. The mixture is cooled, diluted! 15 ml water, cool,! Filter and wash the solid with ethanol-water (1: 1). Light brown crystals are obtained.

Ke 4,7! g of the crude product was added 5 g of potassium hydroxide and 80 ml of ethanol-water (9: 1) and the mixture was refluxed for 3 hours. The mixture is acidified hot! with concentrated hydrochloric acid and diluted! water. After cooling, the light brown crystals are filtered off. The crude product was dissolved in chloroform and the solution was filtered through silica gel. After washing with chloroform, the product was eluted by washing with a mixture of benzene and acetic acid (3: 1) and chloroform and acetic acid (3: 1). The solvent was removed and the product was recrystallized from ethanol. Light brown crystals of m.p. 153 DEG-155 ^DEG C. are obtained.

Example 25

Ethyl 1-p- [2- (p-bromophenoxy) ethyl] aminobenzoate

A mixture of 26.4 g of ethyl p-aminobenzoate, 22.4 g of 2-bromoethyl-p-bromophenyl ether and 80 ml of hexamethylphosphoramide is heated at 100 to 110 ° C for 20 hours. The mixture was cooled, diluted with 25 mL of water, cooled and filtered. The solid was washed with 100 mL of ethanol-water (1: 1), 25 mL of ethanol and water. Light brown crystals of m.p. 128-133 ° C are obtained. Recrystallization from ethanol gave yellow crystals of m.p. 135.5-137 ° C.

Example 26 p- [2- (p-bromophenoxy) ethyl] aminobenzoic acid

A mixture of 10.0 g of ethyl p- (2- (p-bromophenoxy) ethyl) aminobenzoate, 10 g of potassium hydroxide and 100 ml of ethanol-water (9: 1) was refluxed for 3.5 hours. The solid was washed with water to give crystals, m.p. 190-192 ° C. Recrystallization from ethanol (500 ml) gave white crystals, mp 194-196 ° ^C. C.

Example 27 p - [[11-Phenoxy-undecyl] amino] benzoic acid

A mixture of 7.0 g of ethyl p - [(11-phenoxyundecyl) amino] benzoate, 7.0 g of potassium hydroxide and 150 ml of ethanol-water (9: 1) was refluxed for 3.5 hours. The mixture was hot acidified with concentrated hydrochloric acid, diluted with water, cooled, and white crystals of m.p. 117-119 ° C were filtered off. Recrystallization from ethanol gave white crystals of m.p. 118-119.5 ° C.

Example 28

Ethyl p- (2-phenoxyethylamino) benzoate

A mixture of 33 g of ethyl p-aminobenzoate, 80 ml of hexamethylphosphoramide and 20.1 g of β-bromophenetol is heated at 110 ° C for 20 hours. The mixture was cooled, diluted with 25 mL of water and cooled. The solid was filtered, washed with ethanol and water. Crystals having a melting point of 126 to 129 cq are obtained. Recrystallization from ethanol gave pale yellow crystals of m.p. 129-131C.

Example 29 p- (2-phenoxyethylamino) benzoic acid

A mixture of 12 g of ethyl p- (2-phenoxyethylamino) benzoate, 12 g of potassium hydroxide and 1 g of potassium hydroxide. 200 mL of ethanol-water (9: 1) was refluxed for 3.5 hours. The solution was hot acidified with concentrated hydrochloric acid, diluted with water, cooled, filtered and the solid washed with water. Crystals of m.p. to 175 ~ C. Recrystallization from ethanol gave white crystals, m.p. 174-176 ° C.

Example 30

Ethyl p - [(3-phenoxypropyl) amino] benzoate

A mixture of 33 g of ethyl p-aminobenzoate, 21.5 g of 3-bromopropylpropyl ether and 100 ml of hexamethylphosphoramide is heated at 100 to 110 ° C in an oil bath for 20 hours. The mixture was cooled, diluted with 50 ml of water, cooled, the solid was filtered off, washed with ethanol-water (1: 1) and water. Yellow crystals of m.p. 73-74 ° C are obtained.

Example 31 p - [() amino] benzoic acid

A mixture of 15 g of ethyl p - [(3-phenoxypropyl) amino] benzoate, 15 g of potassium hydroxide and 150 ml of ethanol-water (9: 1) was refluxed for 3.5 hours, acidified hot with concentrated hydrochloric acid, diluted water cooled. filtered to give yellow crystals, mp 159-162 C. ^c. Recrystallization from ethanol gives pale yellow crystals, mp 4ání 161-163 ° C.

Example 32

2-Phenoxy-1-propanol

To 200 ml of 1M borohydride in tetrahydrofuran, cooled under nitrogen in an ice bath, 24.9 g of 2-phenoxypropionic acid in 100 ml of dry tetrahydrofuran is added dropwise over 25 minutes. The mixture was allowed to stand at room temperature for 23 hours and then poured onto ice. The mixture was allowed to stand and extracted with dichloromethane. The extracts were dried (MgSO4) and concentrated in vacuo. Obtained as a yellow oil.

Example 33

2-Phenoxy-1-propanol-O-methanesulfonate

To a solution of 15,2 g of 2-phenoxy-1-propanol,

20.8 ml of triethylamine and 300 ml of dichloromethane cooled to -10 ° C in an ice-salt bath were added dropwise with 7.78 ml of methanesulfonyl chloride over 10 minutes. The solution was stirred at -10 ^° C for 30 minutes, washed with 100 mL of ice water, 100 mL of cold 10% hydrochloric acid, 100 mL of cold saturated sodium bicarbonate solution, 100 mL of saturated sodium chloride solution, and dried over magnesium sulfate. The mixture was evaporated in vacuo to give the product as an oil.

Example 34 p - [(2-Phenoxypropyl) amino] benzoic acid

A mixture of 33 g of ethyl p-aminobenzoate, 0.10 mole of 2-phenoxy-l-propanol O-methanesulfonate and 80 ml of hexamethylphosphoramide is heated at 125 ^C for 18 hours. The mixture was cooled, poured into water and extracted with ether. The ethereal extract was washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. The oil was combined with a mixture of 250 ml of ethanol-water (9: 1) and 20 g of potassium hydroxide, and the resulting mixture was refluxed for 3.5 hours. The mixture was acidified with concentrated hydrochloric acid, diluted with water and extracted with chloroform. The chloroform extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. Ethanol was added and the mixture was cooled. The product, m.p. 140 DEG-144 DEG C., is filtered off. Recrystallization gave the product as crystals, m.p. 145-147 ° C.

Example 35

2- [p- (benzyloxy) phenoxy] -2-methylpropionic acid

To a solution of 10.0 g of hydroquinone monobenzyl ether in 40 ml of hexamethylphosphoramide was added 2.7 g of sodium methoxide. The mixture was stirred for 10 minutes and 10.3 g of ethyl 2-bromoisobutyrate was added. The mixture was heated at 120 ° C for 22 hours. It is then allowed to stand and filtered. The solid was dissolved in 150 mL of ethanol-water (9: 1) and 10 g of potassium hydroxide was added. The mixture was refluxed for 6 hours, acidified with concentrated hydrochloric acid and diluted with water. The solid was filtered and washed with water. The obtained crystals were dissolved in aqueous sodium hydroxide and the solution was extracted once with chloroform and once with ether. The aqueous layer was acidified with concentrated hydrochloric acid and the mixture was filtered. The solid was recrystallized from glacial acetic acid. White crystals of m.p. 134-137 ° C are obtained.

Reduction with borohydride in tetrahydrofuran affords 2- [p- (benzyloxy) phenoxy] propan-1-ol which is converted to the O-methanesulfonate. This material is used as an alkylating agent.

Example 36

Ethyl 2- [p- (benzyloxy) phenoxy] propionate

To 20.0 g of p- (benzyloxy) phenol in 80 ml of dry hexamethylphosphoramide was added 5.4 g of sodium methoxide. The mixture was stirred for 10 minutes and 18.1 g of ethyl 2-bromopropionate (exothermic reaction) was added. After 15 minutes, the mixture was heated on a steam bath for 16 hours. The mixture is poured onto ice, the resulting mixture is extracted with ether, the ether extracts are washed with water, dried over magnesium sulphate and dried in vacuo. Give offwhite crystals, mp 36-44 ^e C. Two recrystallizations from ethanol gave off-white crystals, mp 46-49 ° C.

Example 37 p- [2- (2-Naphthyloxy) ethyl] aminobenzoic acid

A mixture of 3.0 g of ethyl p- [2- (2-naphthyloxy) ethyl] aminobenzoate and 3.0 g of potassium hydroxide in 200 ml of ethanol-water (95: 5) was refluxed for 3 hours. The mixture was diluted with 100 mL of water and adjusted to pH 6 with concentrated hydrochloric acid. The mixture was filtered and the solid was washed with 50 mL of water and 20 mL of ice-ethanol-water [4: 1]. M.p. 208-211 ° C.

Example 38

Ethyl 1-4- (2- [4- (chlorophenoxy) propyl] aminobenzoate)

A mixture of 15.1 g of ethyl p-aminobenzoate and 11.3 g of 2- (4-chlorophenoxy) -1-propanol-O-methanesulfonate in 100 ml of hexamethylphosphoramide was added. heated to 115 to 120 ° C for

4.8 hours. The solution was cooled and partitioned between ether and water. The ether layer was separated and the aqueous layer was extracted with ether. The combined ether extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. 23 g of a semi-solid are obtained. An 8 g sample of the residue was chromatographed on silica gel using chloroform as eluent. The first fraction contained 3.8 grams of solid which was chromatographed on a silica gel column using hexane-ethyl acetate as eluent to yield 1.72 g of a light brown solid. A sample (0.45 g) was recrystallized from cyclohexane to give 0.3 g of white needles with a melting point of 96-98 ^° C.

Example 39

Ethyl 1-4 - ([3- (4-chlorophenoxy) propyl] aminobenzoate)

A mixture of 17.1 g of ethyl p-aminobenzoate, 14.6 g

3- (4-chlorophenoxy) -1-propanol-O-methanesulfonate and 100 ml of hexamethylphosphoramide were heated at 110-115 ° C for 16 hours. The solution is diluted with 100 ml of water, allowed to cool and 12.5 g of solid are filtered. Recrystallization from cyclohexane gave 7.8 g of yellow needles. Chromatography on silica gel gave 6.8 g of the product as white crystals, m.p. 87-88 ° C.

Example 40

4 - ([3- (4-Chlorophenoxy) propyl] amino) benzoic acid

A mixture of 4.5 g of ethyl 1-4- (3- (4-chlorophenoxy) propyl) aminobenzoate, 4.5 g of potassium hydroxide and 100 ml of 95% ethanol is refluxed for 3 hours. The solution is acidified with hydrochloric acid and diluted. Recrystallization by dissolving the product in chloroform-ethyl acetate and diluting with hexane gave 13.3 g of the product as off-white crystals, m.p. Mp 180-181 ° C.

Example 41

2- (4-Chlorophenoxy) -1-propanol-O-methanesulfonate

5.7 g of methanesulfonyl chloride were added dropwise to a solution of 8.5 g of 2- (4-chloiphenoxy) -1-propanol, 9.2 g of triethylamine and 250 ml of dichloromethane cooled to -5 DEG. The solution was allowed to stand for 1 hour at room temperature and then washed with 100 ml portions of water, 10% hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. 11.3 g of product are obtained in the form of an oil.

Example 42

3- (4-Chlorophenoxy) -1-propanol-O-methanesulfonate

To a solution of 9.7 g of 3- (4-chlorophenoxy) -1-propanol and 10.5 g of triethylamine in 250 ml of dichloromethane cooled to -5 ° C was added dropwise 6.7 g of methanesulfonyl chloride. The organic layer was dried over magnesium sulphate and the solvent was evaporated in vacuo to give an oily product which crystallized on standing. The solid was collected by filtration and washed with 100 ml portions of water, 10% hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride.

Example 43

4- [2- [4- (Chlorophenoxy) propyl] amino} benzoate

A mixture of 15 g of crude ethyl 4- (2- (4- (chlorophenoxy) propyl) aminobenzoate), 15 g of potassium hydroxide and 100 ml of 95% ethanol was refluxed for 3 hours, cooled, diluted with 100 ml of water and 14 ml was added. Cooling gave 1.8 g of a solid which was recrystallized from hexane-chloroform to give 1.7 g of the product as pale brown crystals, m.p. 160-163 cc.

Example 44

2.3-Dihydroxypropyl 4- (3-phenoxypropylamino) benzoate

A solution of 5.5 g of 4- (3-phenoxypropylamino) benzoic acid, 4.80 g of 25% aqueous sodium hydroxide and 12.6 g of 3-od-1,2-propanediol in 50 ml of hexamethylphosphoramide is stirred at a temperature of 24 hours. The mixture was mixed with water and extracted with ether, and the dried extracts were evaporated to give 2,3-dihydroxypropyl 4- (3-phenoxypropyl lamino) benzoate. as a white solid.

Example 45

2,3-Dihydroxypropyl 4- (3-phenoxypropylamino) benzoate

A solution of 5.5 g of 4- (3-phenoxy) -benzoic acid in 50 ml of hexamethylphosphoramide is treated with 4.80 g of _25/0 aqueous sodium hydroxide and then 11.0 g of 3-chloro-l, 2-propanediol. The resulting mixture was heated at 140 ° C for 6 hours. The mixture was diluted with water and ether and the white solid was filtered off. Recrystallization from acetonitrile gave pure 2,3-dihydroxypropyl 4- (3-phenoxypropylamino) benzoate as a white crystalline solid.

Example 46

2-p-Fluorophenoxypropionic acid

A solution of 15.3 g of 2-bromopropionic acid in 50 ml of dimethoxyethane and 10.5 g of 4-fluorophenol in 50 ml of dimethoxyethane was added to 83 g of sodium hydride in 100 ml of dry dimethoxyethane at 5 ° C. The suspension was refluxed for 6 hours, then cooled and filtered. The crude solid was partitioned between methylene chloride and 1 N hydrochloric acid and the process repeated. The organic layer was dried and evaporated to 50 ml. The crystals were collected, washed with hexane and dried. The melting point is 113-115 cc.

Example 47

2- (p-Fluorophenoxy) propanol

10.2 g of 2- (4-fluorophenoxy) propionic acid in 100 ml of tetrahydrofuran are added to 95 ml of diborane in 95 ml of tetrahydrofuran, and the reaction mixture is stirred at room temperature for 20 hours. The mixture was extracted with 3 x 250 ml) and dried. The solvent was removed in vacuo. A clear liquid is obtained.

Example 48

2- (4-Fluorophenoxy) propyl O-methanesulfonate

To a solution of 7.7 g of 2- (4-fluorophenoxy) propanol and 12.5 ml of triethylamine in 400 ml of methylene chloride at -5 DEG C. was added 8.8 ml of methanesulfonyl chloride. After one hour at 0 ° C to -8 ° C, the mixture was washed with cold water, 10% hydrochloric acid, saturated sodium bicarbonate solution, saturated brine and then dried. A light yellow liquid is obtained. ’

Example 49

Ethyl p-2- (4-fluorophenoxy) propylaminobenzoate

A solution of 11.98 g of 2- (4-fluorophenoxy) propyl 1-O-methanesulfonate and 15.2 g of ethyl 4-aminobenzoate in 200 ml of dry hexamethylphosphoramide is stirred at 120-130 ° C for 46 hours. 200 ml of ether (3.times.) The combined ether layer was extracted with water (3.times.100 ml) and dried, the solution was concentrated and chromatographed on silica gel, eluted with chloroform, evaporated and the residue recrystallized from silica gel. acetone-water and ether for a second time to give a white solid, m.p. 96-98 ° C.

Example 50 p-2- (4-Fluorophenoxy) propylaminobenzoic acid

A solution of 2.6 g of ethyl p- [2- (4-fluorophenoxy) propylaminobenzoate in 100 ml of 95% ethanol containing 2.7 g of potassium hydroxide is refluxed for 2 hours. The reaction mixture was cooled, diluted with 100 ml of water and neutralized with 37% hydrochloric acid. The solid was collected and dried. The white solid obtained was dissolved in 25 ml of chloroform and diluted. 1 ml hexane. 171 DEG-172 DEG C. is obtained.

Example 51

2- [4-Fluorophenoxy) ethanol

To 200 ml of 1 M diborane in tetrahydrofuran are added dropwise to 17.0 g · 4-fluorophenoxyacetic acid in 100 ml of tetrahydrofuran at 5-10 ° ^C C. The reaction mixture was stirred overnight at room temperature and then poured into a mixture of 100 ml of ice and 750 ml of chloroform. The aqueous phase is extracted twice more with 250 ml each time and the combined organic phase is dried. The resulting solution was concentrated to a pale yellow oil. The product is vacuum distilled

14.8 g of distillate.

Example 52

2- (4-Fluorophenoxy) ethyl-O-methanesulfonate

A solution of 125 g of 2- (4-fluorophenoxy) ethanol and 23 ml of triethylamine in 100 ml of methylene chloride at -5 ° C is stirred under nitrogen and 7 ml of methanesulfonyl chloride in 50 ml of methylene chloride are added. The solution was stirred at room temperature for 2 hours, extracted with water, 10% hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic layer was dried and evaporated. A clear liquid is obtained which is used for the alkylation in the following example.

Example · 53

Ethyl p-2- (4-fluorophenoxy) ethylaminobenzoate

A solution of 18 g of 2- (4-fluorophenoxy) ethyl-O-methanesulfonate and 27 g of ethyl 4-aminobenzoate

199 in 150 ml hexamethylphosphoramide was heated at 120 ° C for 2 hours. The reaction mixture was cooled, diluted with 100 mL of water and the solid collected. The solid was recrystallized from methylene chloride-benzene and then again from acetonitrile. A white solid is obtained with a melting point of 122-123 ^° C.

Example 54 p-2- (4-Fluorophenoxy) ethylaminobenzoic acid

Claims (2)

A process for the preparation of aryloxyalkylaminobenzoic acids and their esters of general formula X-O-Y- СО & where it represents Y is a branched or straight alkylene chain of formula C _n H _2n , wherein n is an integer of 2 to 12, R1 is hydrogen, C1-C4 alkyl- or 2,3-dihydroxypropyl, X phenyl-, naphthyl-, thienyl-, furyl-, 1,2,3,4-tetrahydronaphthyl-, 4-chloro-1-naphthyl and substituted phenyl, wherein the phenyl contains halogen, hydroxy, C1-C1 alkoxy as substituents -, C 1 -C 4 alkyl-, cyano-, trihalomethyl-, amino-, C 1 -C 4 alkanoylamino-, C 1 -C 4 alkylamino-, diC 1 - 8 3 To ethyl p-2- (4-fluorophenoxy) ethylaminobenzoate, 6 g KOH in 100 ml 95% EtOH was added. The solution was refluxed for 3 hours and acidified after cooling with 9 ml of concentrated hydrochloric acid. The solution is diluted with 50 ml of water. The solid is collected and recrystallized first from a mixture of acetonitrile and ethyl acetate and then from a mixture of tetrahydrofuran and hexane. A white powder is obtained with a melting point of 209-210 ^° C. OF THE INVENTION —Cialkylamino-, phenoxy-, p-chlorophenoxy-, benzyloxy-, p-chlorobenzyloxy- or C8-C1 cycloalkyl, and when R1 is hydrogen, their alkali metal salts or organic bases, characterized in that the derivative of p aminobenzoic acid of formula ^NH i ~ © - ^ ^what i wherein R is as defined above, is reacted with an alkylating agent capable of introducing a group X-O-Y-, wherein X and Y have the abovementioned meanings, at from 50 to 170 ^L C for 1 to 25 hours. 2. A process according to claim 1 wherein the reaction is carried out in the presence of a solvent.