DK141844B - Analogous process for preparing a 4- (monoalkylamino) benzoic acid derivative. - Google Patents

Description

U1844 i

The present invention relates to an analogous process for the preparation of a novel 4- (monoalkylamino) benzoic acid derivative, such as a 4- (monoalkylamino) benzoic acid ester, of the general formula 5 R 1 -N-H

R 2 is a straight or branched alkyl group having 2 to 19 carbon atoms, R is hydrogen, alkyl or 1-4 carbon atoms or dialkylaminoethyl having 1-4 carbon atoms in the alkyl moieties, or pharmacologically acceptable salts thereof with bases or acids. By such alkyl groups is understood e.g. methyl, isopropyl, n-propyl, ethyl, sec-butyl, tert-amyl and n-hexyl.

It has been found in animal experiments that the compounds prepared by the method of the invention possess hypolipidemic activity. Compounds 20 of the above Formula I have been found to possess hypolipidemic activity in animals, and in particular, they are serum triglyceride lowering and cholesterol lowering active when R 1 contains 14-17 carbon atoms. Therefore, of the active compounds, the preferred group comprises, in particular, such compounds wherein R 1 contains 14-17 carbon atoms and where R is hydrogen. The compounds of the invention can be used either as the free acids or in the form of a pharmaceutically acceptable salt. Since the compounds are amphoteric, the salts can be formed with the acidic or basic moiety. The salts may be either of inorganic nature such as the ammonium salt, sodium salt or potassium salt of the carboxylic acid group or hydrochloric acid salts or the sulfuric acid salts of the amino group, or3, are of an organic type such as an organic amine salt of the carboxylic acid group 2

U18U

or a trifluoroacetic acid salt or citric acid salt of the amino group.

Substantial efforts have been made in recent years to find drugs that are useful in the treatment of hyperlipidemia, resulting in elevated blood cholesterol, phospholipid and / or triglyceride levels. This condition is associated with a number of diseases, one of the most severe being arteriosclerosis. Medications used to lower blood cholesterol, phospholipid and triglyceride levels are called hypolipidemic agents. Currently, there are three more significant lipid-lowering agents: clofibrate, D-thyroxine and nicotinic acid. The type of compounds prepared by the process of the invention are 4- (monoalkylamino) benzoic acids as well as esters and salts thereof.

Heretofore, it has not been known that the related known compounds in which R 1 contains 1 to 7 carbon atoms should possess hypolipidemic activity. Thus, it is surprising when it has now been found that the novel compounds containing 8 to 19 carbon atoms possess hypolipidemic activity.

The 4- (monoalkylamino) benzoic acids and esters produced by the process of the invention are generally colorless or golden brown crystalline solids (some being colorless or golden brown oils), with characteristic melting points and spectral properties. They are soluble in organic solvents such as chloroform, benzene, dichloromethane, N, N-dimethylformamide, dimethyl sulfoxide and lower alkanols. However, they are usually insoluble in water.

The 4- (monoalkylamino) benzoic acids and esters prepared by the process of the invention are bases and can be converted to their non-toxic acid addition salts by treatment with acids such as sulfuric acid, hydrochloric acid, phosphorus

phoric acid, succinic or citric acid. The compounds in which R

3 141844 is hydrogen, can be reacted with inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide and ammonium hydroxide or organic bases such as lower mono-, di- or tri- (lower alkyl) amines such as methylamine, diethylamine, trimethylamine, dibutylamine or Ν, Ν -dimethylethylenediamine to give the corresponding carboxylic acid salts.

4- (Monoalkylamino) benzoic acid derivatives of formula I are prepared by the process of the invention, characterized in that p-aminobenzoic acid or an ester or salt thereof of formula ΝΗ defined, a) is alkylated by treatment with an alkylating agent of the formula R 1 X wherein R 1 is as defined above and X is halogen, hydroxy, alkyl or arylsulfonate ester or trialkyl ammonium, b) acylated by treatment with a acylating agent of the formula R3COX3 wherein R is alkyl of 7-18 carbon atoms and X is as defined above and the resulting product of the formula

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30 I

ksy III

co2r2 is then reduced to form a compound of formula I, or c) is added to an episulfide of formula CH1 - CH-R4

"V

4 wherein R is alkyl of 6 to 17 carbon atoms, onto which is formed the product of formula 4 141864

SH

HN-CHOCHR4 Φ

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5 CO 2 R

2 wherein R and R are as defined above are reduced to remove the mercapto group at the 2-position of the 4-N-alkyl group, whereupon, if desired, an ester of the formula I thus formed is saponified to the free acid, or the acid with the formula I is esterified, or the acid is converted to its salt with a base or an acid addition salt is formed.

In particular, alkyl 4- (monoalkylamino) benzoates are prepared by alkylating alkyl β-aminobenzoates of formula II with appropriate alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates with or without solvent at 50 ° C-150 ° C. Suitable solvents are lower alkanols, chloroform, Ν, Ν-dimethylformamide, N, N-dimethylacetamide, diglyme, dimethyl sulphoxide, acetonitrile, toluene, benzene and hexamethylphosphoramide. The reaction can be carried out with an equivalent amount of base such as an alkali carbonate or bicarbonate or with a catalytic amount of copper powder when using alkyl halides as an alkylating agent.

Alternatively, the alkyl 4- (monoalkylamino) benzoates 25 can be prepared by reacting an alkylaminobenzoate with an alkyl halide of 8-19 carbon atoms after the formation of amine anion by an equivalent amount of sodium hydride in an inert solvent such as N, N-dimethyl. formamide, Ν, Ν-dimethylacetamide and diglyme at 50-150 ° C.

In method b), reductive alkylation of a 4-aminobenzoate ester of formula II is carried out via metal hydride reduction of a 4- (acylamino) benzoate ester or acid of formula III. The aldehyde appears to be formed in small amounts in situ in the synthesis which includes heating at elevated temperature 35 and pressure of n-hexadecanol and methyl 4-aminobenzoate in the vicinity of an activated Raney nickel catalyst to give methyl-4 - (n-hexadecylara ± no) benzoate. Diborane reduction of ethyl 4- (n-hexadecanoylamino) benzoate at room temperature or above for 1-6 hours gives the ethyl analog of the above ester.

The 4- (alkylamino) benzoic acids of the invention are prepared by hydrolysis of the corresponding benzoate esters by reaction with an alkali hydroxide such as sodium or potassium hydroxide in a lower alkanol, water or an aqueous lower alkanol at 25-150 ° C. Alternatively, the 4- (alkylamino) benzoic acids can be precipitated by hydrolysis of the lower alkyl 4- (monoalkylamino) benzoates with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid in water or aqueous lower alkanols.

The lower alkyl-4- (dialkylamino) benzoates or 4- (dialkylamino) benzoic acids have lower activity than the compounds prepared by the process of the invention.

The acyl acyl monoalkylaminobenzoates such as e.g.

20 alkanoyl or substituted alkanoyl or aroyl and substituted. The aryl derivatives also have lower activity than the compounds of the invention.

The mechanism of the activity of 4- (monoalkylamino) benzoic acid compounds is not known. However, it has been found that the compounds prepared by the method of the invention have hypolipidemic activity as determined in animal experiments as follows: the compounds tested were administered orally to the diet of groups of 4-6 male rats, CFE strain of Carworth Farms, 30 New. City, New York. A control group of 6-8 rats was kept on the diet alone; the sample group was kept on the diet plus the indicated percentage of compound by weight. After 6 days or 2-4 weeks of treatment, serum sterol concentrations were determined either (1) according to the saponification and extraction method set forth by P. Trinder in Analyst 77, 321 (1952) and by Zlatkis et al in J.Lab.Clin. With. 44, 486 (1953), colorimetric determination or (2) using the method of H.H. Leffler in Amer. J. Clin. Path. 31, 310 (1959) extraction method and Zlatkis (see above) colorimetric determination, the whole method being suitably modified for use with an automatic mechanical analyzer. Serum triglycerides were calculated using the automated method set forth by Kessler and Lederer in "Automation in Analytical Chemistry" Skeggs, L. T., (Ed.), Mediad, Inc., New York, 1965, page 341. The Phos-10 pholipids were determined by standard methods (G. R. Bartlett, J. Biol. Chem. 234, 466 (1959)). Changes in serum lipids are expressed as a percentage reduction relative to the control group.

In these experiments, a compound is considered to have hypolipidemic activity if it decreases serum sterol values 15% or more below the control animals and / or decreases triglyceride values 25% or more below the control animals. Table I shows several of the compounds of the invention as well as the extent to which they decrease serum sterol and triglyceride values after 1 week and 4 weeks administration and phospholipids after 4 weeks administration.

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The data in Table I indicate that the tested 4- (monoalkylamino) benzoic acids and their derivatives are all effective hypolipidemic agents, ie. they decrease serum triglyceride and / or sterol levels. Reduction of serum 5 sterol is clinically highly desirable, as virtually all major studies in the literature indicate that elevated serum sterol concentration is directly linked to the development of other arteriosclerosis. Of the clinical types of hyperlipoproteinemia that have been described so far, the majority of the lipids found in abnormal values are sterol and triglycerides. The preferred compounds of the invention are capable of decreasing both these blood lipid fractions and phospholipids, the third major lipid component of the blood.

The effects of one of the compounds (4- (n-hexadecylamino) benzoic acid) prepared according to the invention on serum lipid values are determined in mice and jump mice (Table II) after 1 week of treatment. Mice (CF-1 strain) are procured from Carworth Farms, New City, New York, and 20 mare are purchased from Chick Line Co., Vineland,

New Jersey. The methods used for lipid analysis are the same as listed above for Table I.

Table II 25

Springmus Mouse

Dose, percent of diet 0.1 0.1 serum sterol,% reduction 20 22 serum phospholipid,% reduction - 28 30 4- (Monoalkylamino) benzoic acids and derivatives prepared according to the invention have degrees similar to or greater than l-methyl 4-piperidyl-bis- (p -chlorophenoxy) acetate and clofibrate, and thus are valuable as hypolipidemic compounds in mammals when administered in amounts ranging from ca. 0.5 mg per kg to approx. 40 mg per kg body weight per day. A preferred cure dosage for ίο 14ί844 to achieve optimal results ranges from approx. 2 mg per kg to approx. 29 mg per kg. Thus, the daily dose to a subject of approx. 70 kg body weight be approx. 35 mg ~ ca. 2.8 g and preferably approx. 140 mg - 2.0 g.

The invention is further illustrated by the following examples.

Example 1 4- (n-Dodecylamino) benzoic acid 10 A solution consisting of 10.4 g of potassium hydroxide in 200 ml of 90% aqueous ethanol is added to a solution of 25.4 g of 4-aminobenzoic acid in 200 ml of 90% ethanol.

When the solid is completely dissolved, 44.3 ml of 1-bromododecane and 25.5 g of potassium carbonate are added and the mixture is refluxed for 25 hours. An additional 44 ml of 1-bromododecane is then added and heating is continued for 30 hours.

The crude product is frozen for ester by adding 31.2 g of potassium hydroxide in 100 ml of water and reflux for 24 hours. The acid is precipitated by the addition of 160 ml of concentrated hydrochloric acid followed by 200 ml of water and cooling.

The filtered material is slurried in chloroform to give a white solid which is recrystallized from 95% aqueous ethanol to give 2.95 g of 4- (n-dodecyl-amino) benzoic acid as white crystals, m.p. 111.5-25 113, 125-125 ° C. Double melting points are obtained because the products are liquid crystals, which is characteristic of this class of compounds.

The chloroform filtrate is dried and the resulting solid is washed with pentane. The insoluble material is recrystallized from 95% aqueous ethanol to give 3.10 g of 4- (n-dodecylamino) benzoic acid as whitish flakes, m.p. as stated above. The pentane filtrate is dried and the resulting solid is recrystallized from benzene to give 9.40 g of 4- (n-dodecylamino) benzoic acid, 35 m.p. as stated above.

141844 11

Example 2

Ethyl 4- (n-thxidecylamino) benzoate

A mixture consisting of 47.0 g of ethyl 4-amino-benzoate, 72.8 ml of 1-bromotridecane and 39.3 g of potassium parbonate 5 in 500 ml of dry N, N-dimethylacetamide is heated (130 ° C) under nitrogen for 24 hours. The reaction mixture is cooled, filtered and the solid product is washed once with cold absolute ethanol and food water. Additional product is obtained by addition o? water to the filtrate and wash twice with absolute ethanol. The total yield of ethyl 4- (n - tridecylamino) benzoate is 66.5 g of white crystals.

Example 3 4- (n-Tridecylamino) -benzoic acid A mixture consisting of 27.7 g of ethyl 4- (n-tridecylamino) benzoate and 44.7 g of potassium hydroxide in 450 ml of water-ethanol (1: 1) is refluxed for 6 hours. Concentrated hydrochloric acid (80 ml) is added to the hot mixture, which is then cooled, diluted with water and filtered. Recrystallization from absolute ethanol and from ethanol benzene (1: 1) gives 16.5 g of 4- (n-tridecylamino) benzoic acid as white crystals, m.p. 106-9; 112-113 ° C. The double point of measurement p. liquid crystals, cf. Example 1.

Example 4

Ethyl 4- (n-tetradecylamino) benzoate

A mixture of 16.5 g of ethyl 4-amino-benzoate and 30 g of 1-bromotetradecane is heated in a steam bath for 19 hours. Ethanol is added and the mixture is filtered.

The solid is washed with ethanol, water, 0.1N sodium hydroxide and with water to give 9.0 g of white crystals. The filtrate is made basic, filtered and the solid washed with ethanol to give 1.7 g of crystals.

The two quantities are recrystallized from ethanol to give 8.75 g of white ethyl 4- (n-tetradecylamino) benzoate, m.p. 81-82 ° C.

12 141844

Example 5 4- (n-Tetradecyl amino) benzoic acid

To a solution consisting of 16.5 g of ethyl 4-aminobenzoate in 150 ml of dry Ν, Ν-dimethylformamide was added 4.12 g of sodium hydride (56% in oil) and 27.7 g of 1-bromotane trecan. The mixture is heated in a steam bath until hydrogen evolution begins, and then cooled for a short time to regulate the reaction. After the sodium hydride is reacted, the mixture is heated on a steam bath under nitrogen for 10 6 hours. The mixture is cooled, filtered and the solid washed with ethanol and with water to give 21.75 g (59%) of ethyl 4- (n-tetradecylamino) benzoate, m.p. 81-82 ° C.

A mixture of 29 g of ethyl 4- (n-tetra-decylamino) benzoate, 28 g of potassium hydroxide and 500 ml of 50% ethanol is refluxed for 6 hours. The mixture is acidified with concentrated hydrochloric acid, cooled and filtered to give golden brown crystals. Recrystallization from ethanol gives 15.1 g of white 4- (n-tetradecylamino) benzoic acid, m.p. 108-111 ° C.

20

Example 6

Ethyl 4- (n-pentadecylamino) benzoate

A mixture of 49.5 g of ethyl 4-amino-benzoate, 87.3 g of 1-bromopentadecane and 41.4 g of potassium carbonate 25 in 550 ml of Ν, Ν-dimethylacetamide is heated (135 ° C) under nitrogen for 24 hours. The reaction mixture is cooled, filtered and the solid washed with cold absolute ethanol, with water and dried in air. Recrystallization from absolute ethanol gives 58.8 g of white ethyl 4- (n-pentadecylamino) benzoate, m.p. 73 to 74.5 ° C.

Example 7 4- (n-Pentadecylamino) -benzoic acid

A mixture of 58.8 g of ethyl 4- (n-35-pentadecylamino) benzoate and 87.5 g of potassium hydroxide in 900 ml of water ethanol (1: 1) is refluxed for 6 hours. Concentrated hydrochloric acid (140 ml) is added to the hot solution followed by 600 ml of water and the mixture is cooled.

The product is collected, washed well with water and recrystallized from benzene-ethanol (1: 1) to give 42.5 g of white 4- (n-pentadecylamino) benzoic acid, m.p. 107-108 ° C, 5 126-126.5 ° C.

Example 8

Ethyl 4- (n-hexadecylamino) benzoate

A solution of 49.5 g of ethyl 4-amino-benzoate and 45.8 ml of 1-bromohexadecane in 525 ml of absolute ethanol is refluxed overnight. The reaction mixture is cooled and the filtered product is recrystallized from 750 ml of absolute ethanol to give 16.5 g of ethyl 4- (n-hexadecylamino) benzoate as white crystals, m.p. 84-86.5 ° C ..

15 '.....

Example 9

Ethyl 4- (n-hexadecylamino) benzoate

A mixture consisting of 33.0 g of ethyl 4-amino-benzoate, 61.0 g of 1-bromohexadecane, 21.2 g of sodium carbonate 20 and 300 ml of ethanol is refluxed for 24 hours. The mixture is cooled and filtered. The solid is washed with 250 real cold ethanol and with 1 liter of water to give 20 g of white ethyl 4- (n-hexadecylamino) benzoate, m.p. 81-84 ° C, Example 10

Ethyl 4- (n-hexadecylamino) benzoate

A mixture of 33.0 g of ethyl 4-aminobenzoate, 61.0 g of 1-bromohexadecane, 27.6 g of potassium carbonate and 400 ml of dry ethanol is refluxed for 23 hours. An additional 61 g of 1-bromohexadecane is added and the mixture refluxed for an additional 32 hours. The mixture is cooled, filtered and the solid washed with 250 ml of cold ethanol and with 1 liter of water to give 30.6 g of white ethyl 4- (n-hexadecylamino) benzoate, m.p. 80-83 ° C.

Ϊ4Ι844 14

Example 11 4- (η-Hexadecylamino) -benzoic acid

A mixture consisting of 5.85 g of ethyl 4- (n - hexadecylamino) benzoate and 4.21 g of potassium hydroxide in 5 150 ml of water ethanol (1: 1) is refluxed for 6.5 hours.

Concentrated hydrochloric acid (40 ml) is added to the hot solution followed by cooling, adding 100 ml of water and cooling to give the corresponding chloride. This is recrystallized from ethanol-water (9: 1) to give 5.0 g of white 4- (n-hexadecylamino) benzoic acid (m.p.

107-110 ° C, 124-127.5 ° C). Double melting point p.g.a. liquid crystals, cf. Example 1.

Example 12 4- (n-Hexadecylamino) -benzoic acid

To a mixture of 13.7 g of 4-amino-benzoic acid and 5.61 g of potassium hydroxide in 150 ml of 90% aqueous ethanol is added 33.6 ml of 1-bromohexadecane and the mixture is refluxed for 25 hours. A solution of 28 g of potassium hydroxide in 150 ml of 90% aqueous ethanol and 100 ml of water is added. The mixture is refluxed for 24 hours and 35 ml of concentrated hydrochloric acid is added to the hot solution. Cooling and filtration give a product which is washed with water and dried. Recrystallization from benzene 25 gives 10.7 g of 4- (n-hexadecylamino) benzoic acid, m.p. 106-108 ° C, completely melted at 125-127 ° C. Double melting point as in Example 1.

Example 13 Ethyl 4- (n-heptadecylamino) benzoate

A mixture of 48.3 g of ethyl 4-amino-benzoate, 93.4 g of 1-bromoheptadecane and 40.4 g of potassium carbonate in 700 ml of absolute ethanol is refluxed for 24 hours. The reaction mixture is then cooled, filtered, and the solid is washed with cold absolute ethanol and then with water until neutral. The product is pure ethyl 4- (n-hep-tadecylamino) benzoate.

141844 15

Example 14 4- (n-Heptadecylamino) -benzoic acid

A mixture of 48.3 g of ethyl 4-amino-benzoate, 93.4 g of 1-bromoheptadecane and 40.4 g of potassium carbonate 5 in 700 ml of absolute ethanol is refluxed for 24 hours. The reaction mixture is cooled, filtered and the solid is washed with cold absolute ethanol and with water to give 27.9 g of ethyl 4- (n-heptadecylamino) benzoate as white flakes. A mixture consisting of 27.9 g of this ester, 10 38.8 g of potassium hydroxide and 400 ml of ethanol-water (1: 1) is refluxed for 6.5 hours. To the hot solution is added 65 ml of concentrated hydrochloric acid. The mixture is diluted with 400 ml of water, cooled and filtered to give 25.2 g of white crystals. Recrystallization from 300 ml of benzene-15-ethanol (1: 1) gives 21.7 g of 4- (n-heptadecylamino) -benzoic acid, m.p. 105-108 ° C; 128 to 128.5 ° C. Thus double melting point as in Example 1.

Example 15 Ethyl 4- (n-octadecylamino) benzoate

A mixture consisting of 66 g of ethyl 4-amino-benzoate, 133.4 g of 1-bromooctadecane, 55 g of potassium carbonate and 550 ml of Ν, Ν-dimethylacetamide is heated at 135 ° C for 20 hours. The mixture is cooled, filtered and the solid is washed with cold ethanol. Recrystallization from ethanol gives 98 g of the product. Recrystallization from benzene - ethanol (1: 1) gives 67 g of ethyl 4- (n-octadecylamino) benzoate as white crystals, m.p. 88-89 ° C.

Example 16 4- (n-Octadecylamino) -benzoic acid

A mixture consisting of 33 g of ethyl 4-amino-benzoate, 67 g of 1-bromooctadecane, 27.6 g of potassium carbonate and 400 ml of Ν, Ν-dimethylacetamide is heated at 130-155 ° C for 18 hours. The mixture is cooled, filtered and the solid washed with water and slurried in 100 ml of ethanol to give 38 g of white crystals.

141844 16

The crystals are combined with 56 g of potassium hydroxide,

1000 ml of ethanol-water (1: 1) and the mixture is refluxed for 7 hours. While the mixture is still warm, slowly add 100 ml of concentrated hydrochloric acid to the mixture followed by 200 ml of water, cooling and filtration to give 40 g of white crystals. Recrystallization from benzene and then from ethanol gives 22.6 g of 4- (n-octadecylamino) benzoic acid, m.p. 103-106 ° C, completely melted at 123-126 ° C

Example 17

Ethyl 4- (n-nonadecylamino) benzoate

A mixture consisting of 40.4 g of ethyl 4-amino-benzoate, 85.2 g of 1-bromnonadecane and 33.8 g of potassium carbonate in 400 ml of dry N, N-dimethylacetamide is heated under nitrogen at 130 ° C for 24 hours. The mixture is cooled, filtered and the solid is washed with cold absolute ethanol and then with water. The product is recrystallized from absolute ethanol to give 79.1 g of white ethyl 4- (n-nonadecylamino) benzoate.

20

Example 18 4- (n-Nonadecylamino) -benzoic acid

A mixture of 79.1 g of ethyl 4- (n-nonadecylamino) benzoate and 103 g of potassium hydroxide in 1200 ml of 50% ethanol is refluxed for 6 hours. Hydrochloric acid (170 ml) is then added to the hot solution and the mixture is diluted with 300 ml of water, cooled and filtered. Recrystallization from benzene-ethanol (1: 1) gives 67.4 g of white 4- (n-nonadecylamino) benzoic acid, m.p. 104-106 ° C; 120-124 ° C.

30

Example 19

Ethyl 4 - [(1-methylundecyl) amino] benzoate

A mixture consisting of 49.6 g of ethyl 4-amino-benzoate, 74.9 g of 2-bromododecane and 41.5 g of potassium carbonate in 550 ml of N, Kr-dimethylacetamide is heated at 130 ° C for 24 hours.

The reaction mixture is reduced to a small volume by distillation under large vacuum. Water and ethanol are added and the mixture is cooled. The product is collected, washed with water and recrystallized from absolute ethanol followed by chromatography on silica gel in chloroform solution. The fractions containing the product are combined and the solvent removed in vacuo. The yield is 15.0 g of ethyl 4 - [(1-methylundecyl) amino] benzoate.

Example 20 4 - [(1-Methylundecyl) amino] benzoic acid 10 A mixture consisting of 15.0 g of ethyl 4 - [(1-methylundecyl) amino] benzoate and 25.2 g of potassium hydroxide in 175 ml of 50% The aqueous ethanol is refluxed for 6 hours.

37 ml of concentrated hydrochloric acid is added to the hot reaction mixture and the product is precipitated by cooling.

The filtered product is recrystallized from absolute ethanol to give 7.70 g of 4 - [(1-methylundecyl) amino] benzoic acid, m.p. 76.5 to 78.5 ° C.

Example 21 Dimethylaminoethyl-4- (n-hexadecylamino) benzoate, hydrochloride

To 90 ml of thionyl chloride cooled to 0 ° C is added portionwise 21.7 g (0.060 mol) of 4- (n-hexadecylamino) benzoic acid. To the viscous mass is added 100 ml of toluene. After stirring overnight (16.5 hours), the solvent is removed under vacuum. 50 ml of toluene are added and the solvent removed under vacuum. Nitrogen is bubbled through the residual oil to which 100 ml of toluene is added and the solution is cooled. 6.24 g (0.040 mol) of 2-dimethyl-aminoethanol are added to the mixture. The mixture is stirred at room temperature for 4.5 hours, diluted with ether and stirred for 1 hour. Cooling and filtration give a solid which is washed with ether and with water to give 7.0 g of golden-brown crystals. Twice recrystallization from ethanol 35 gives 5.2 g of golden brown crystals, m.p. 162-165 ° C with prior sintering.

18

U18M

Example 22

Ethyl 4- (n ~ octylaiid.no) benzoate

A mixture of 33 g (0.20 mol) of ethyl 4-aminobenzoate, 44 ml of 1-bromooctane and 0.50 g of copper powder is heated in a steam bath for 19 hours. The mixture is cooled, diluted with ethanol, filtered and the solid is washed with cold ethanol and with water to give golden-brown crystals. The filtrate is neutralized with ION potassium hydroxide, cooled and filtered, and the solid is washed with water and with ethanol to give golden brown crystals. The two portions of crystals are combined to give 16 g of the product. The mother liquors from the two portions of crystals are combined, diluted with water and extracted with ether. The ether extracts are washed with water, with 1N hydrochloric acid and with water. The ether extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is diluted with ethanol, cooled and filtered to give 3.7 g of the product. The two portions of products (19.7 g) are combined and recrystallized from ethanol to give 15.1 g of white crystals, m.p. 79-80 ° C.

Example 23 4- (n-Octylamino) -benzoic acid

A mixture of 3.0 g of ethyl 4- (n-octyl-amino) benzoate, 3 g of potassium hydroxide and 50 ml of ethanol-water (9: 1) is refluxed for 3 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with water and filtered.

The solid is thoroughly washed with water and recrystallized from ethanol to give 2.1 g of 4- (n-octylamino) benzoic acid as white crystals, m.p. 117-118 ° C.

141844 19

Example 24 4-Hexadecylaminobenzoic acid 50 "

HnJc15H31 HfCC15H31 Λ, ™ Λ I l) + NaH-> + B2H6 C-OH C

II

O 0 h1? C16H33 15 THF_ ^

2) HCl I

V

C-OH

n 20 0 1 mg of 4-Hexadecanoylaminobenzoic acid is introduced into a slurry of 22.5 mg of 57% sodium hydride (washed twice with hexane) in 20 ml of dry THF under nitrogen.

The reaction mixture is stirred for 15 minutes at room temperature and heated to reflux for one hour. The slurry is cooled to room temperature and 2 ml of 1M diborane in THF is added. The slurry is then heated to reflux for 16 hours. The solution is then cooled, and 10 ml of saturated ethanolic HCl is introduced. The solution is then heated to reflux for one hour and evaporated. The hydrolysis was then repeated with fresh HCl and the solution evaporated to a thick swell. This slurry is diluted with 10 ml of H 2 O and Et 2 O. The diethyl ether solution is evaporated and the solid recrystallized to give 4-hexadecylaminobenzoic acid.

T4T84A

20

Example 25

Ethyl p-hexadecylaminobenzoate 5 HNC0C15H51 ®Fl6H33 ~ n f ^^ jj + BH ^ THP-> jj C02Et C02Et 10

To 100 ml of diborane in tetrahydrofuran (0.1 mol 'BH3) cooled to 0 ° is added dropwise 0.05 mol of ethyl 4-hexadecanoylarainobenzoate in 100 ml of tetrahydrofuran. The mixture is refluxed for 20 hours and ethanolic 15 hydrochloric acid is added. The mixture is refluxed for one hour and the solvent removed. The residue is made basic and purified to give ethyl p-hexadecylaminobenzoate as white crystals, m.p. 85 ° C and 86 ° C.

Example 26 4-Hexadecylaminobenzoic acid nh2

AgNO

I + - »25 S 2

T (C, H), N

C-OH 5 3

"2) H9S

0 * 30

SH

HK-CH2CHCl4H29 B? C16H33 35 I Raney Ni '* i

V V

C-OH · COH

il II

Island Island

141844 21

An aqueous mixture of 34 parts AgNO 4, 53 parts triethylamine and 31.4 parts 4-aminobenzoic acid in 160 ml H2 O is worked up and 46.2 parts hexadecylene sulfide are added. The reaction mixture is stirred overnight at 50 ° C and 5 H 2 S is bubbled through it. The solution is then filtered and the product is reacted with 580 g of Raney nickel in 1000 ml of ethanol-water solution at reflux for 16 hours. The reaction mixture is then cooled and filtered. The solution is evaporated to dryness to give 4-hexadecylamibo-benzoic acid, m.p. 108-110 ° C and 126-128 ° C.

Example 27 NH-NH-C, cH, 15 in 2 µl 33 33 / k Dioxane

f |] + C16H330H + Ki Δ I

V V

C-OC2H5 £ "* OC2H5 20 o 0 J« HC16H33

Ha + KOH -> Μ 25

C-OH

N

ISLAND

Wash 24.4 g of activated Raney nickel several times with water until the alkalinity has disappeared and then put on a three-necked 250 ml flask. 100 ml of dioxane is added and the slurry is partially distilled under nitrogen until a flask temperature of 101 ° C is reached. 1.65 parts of ethyl 4-aminobenzoate and 24.4 parts of 1-hexadecanol are introduced and the slurry is heated under reflux under the nitrogen. for 14 hours. The slurry is then partially cooled and filtered. The dioxane is evaporated. The residual solid is then heated at the same weight of KOH in 100 ml of 95% ethanol for three hours under reflux. The solution 5 is neutralized to pH 6.0 with 37% HCl and diluted with 150 ml of water to give 4-hexadecylaminobenzoic acid.

Example 28 N sodium 4-hexadecylaminobenzoate 1. 1.0N sodium methoxide solution: dissolve 54 g (1.0 mol) in ethanol and make up to a volume of 1 liter.

2. Pour 2-3 liters of ethanol into a 4 liter beaker equipped with stirrer and add 250 g (0.691 mol) of 4-N-hexadecylaminobenzoic acid. To this mixture 15 is added slowly with constant stirring 725 ml of the 1.0N sodium methoxide solution. The mixture is stirred for at least one hour, 3. After stirring, the solids are collected by filtration and washed with three 100 ml portions of cold ethanol. The solids are sucked dry for approx. one hour.

Claims (3)

141844 Analogous Process for Preparing a 4- (Monoalkylamino) Benzoic Acid Derivative of the General Formula Wherein R1 is a straight or branched alkyl group of 2 to 19 carbon atoms, R is hydrogen, alkyl of 1-4 carbon atoms or dialkylaminoethyl of 1 to 4 carbon atoms in the alkyl moieties, or pharmacologically acceptable salts thereof with bases or acids, characterized in that p-15-aminobenzoic acid or an ester or salt thereof of formula NB ', φ - 20 T CO 2 R 2 wherein R is as defined above, a) is alkylated by treatment with an alkylating agent of formula RX wherein R is as defined above and X is halogen, hydroxy, alkyl or arylsulfonate ester or trialkylammonium, b) acylated by treatment with an acylating agent of formula r3cox3 wherein R is alkyl of 7-18 carbon atoms and X is as defined above and the resulting product of formula 0 "3 HN-CR 35 111 co2R2