NO123845B - - Google Patents

Description

Analogy method in the production of

therapeutically active phenylsalicylic acid compounds.

The present invention relates to an analogue method by

preparation of 5-(^-fluorophenyl)-salicylic acid and its O-acetyl derivatives with the general formula:

where A is hydrogen or acetyl. These compounds are useful as anti-inflammatory agents, are effective in preventing or inhibiting dropsy and granulomatous formation. and has.a useful antipyretic and analgesic activity.

A closely related compound, -5-phenylsalicylic acid, is known

from the U.S. patents 2.-7<1>+^.916 and 3.123.5^3. However, as can be seen from the trial results set out below, the method compounds are significantly more anti-inflammatory active than the known compound.

From French patent 3^81M it is known that 3_(p-fluorobenzyl)-salicylic acid methyl ester and -methyl ether are anti-inflammatory active, but these are completely different from the present biphenylyl compounds in that they have a methylene group between the two benzene rings.

Present process compounds of formula I are obtained by a parent compound of the general formula.:

where M is a metal ion, e.g. an element of. groups IA and B, IIA and B or VIII of the periodic table, such as lithium, sodium, potassium, rubidium, cesium, copper (i.e. cupro), calcium, magnesium, aluminium, zinc or iron (i.e. ferro), or the Grignard radical , -MgX, where X is halogen or OR', where R' is alkyl, aryl, alkenyl, alkynyl, aralkyl or acyl (i.e., allphatic acyl, such as alkanoyl or aromatic acyl such as aroyl), and R is hydroxy, -OM where M is as indicated above, or an α-hydroperoxy group of the general formula:

where R" is alkyl, ... aralkyl or aryl, is reacted with an acid, optionally during simultaneous or subsequent acetylation.

The preferred compounds are those in which M is an alkali metal (eg sodium or potassium) and R is hydroxy or oc-hydroperoxy-sec-alkyl.

The salts of the precursors of formula II are treated with aqueous or non-aqueous acid to form 5-(^-fluorophenyl)-salicylic acid. Although widely varying precursors as defined above can be used, alkali 2-(α-hydroperoxy-sec.-alkyl)-5-(^-fluorophenyl)-benzoates, alkali-^-C^f-fluorophenyl)-salicylates and magnesium, ferrous or cupro-5-C+-fluorophenyl) salicylates of particular value. When the desired product is acetyl-5-C+-fluorophenyl)-salicylic acid, the salts of its precursors in acetic anhydride are treated with an acid to give acetyl-5-(^-fluorophenyl)-salicylic acid. Other acetylating agents such as enol acetates, acetyl halides or ketenes can be used instead of acetic anhydride.

The general procedure for preparing the compound of formula I is to treat a precursor compound of formula II with an acid, either with or without the addition of promoters and other reagents. The precursor can be prepared and processed in solution (aqueous and/or non-aqueous) without isolation. When elevated temperatures are used in the reaction, they must be just above room temperature and include reflux temperatures and temperatures up to those at which unwanted decomposition occurs. The reaction time can vary from several minutes to several hours or days depending on the reaction rate and the desired degree of conversion. The product of formula I can be recovered from the reaction medium by conventional methods including filtration, crystallization or evaporation. The reaction can be carried out batchwise or continuously in suitable equipment.

Examples of usable acids include organic acids,

such as glacial acetic acid, halogen-substituted acetic acids, lower alkanoic acids and citric acid, and inorganic acids, such as sulfuric acid, hydrochloric acid, phosphoric acid, hydrobromide, hydrofluoric acid and other strong acids. These acids can be used individually or in combination. In general, the desired carboxylic acid derivatives can be easily displaced from their salts by acids with ionization constants greater than that of the desired carboxylic acid. Of particular value are the mineral acids. The amount of acid can be from 0.1 mol to as much as is economically justifiable per mole precursors. In the case of strong acids, the molar ratios are preferably of the order of magnitude from 0.5 to 10 moles of acid per mole precursors.

Acyclic, carbocyclic and heterocyclic compounds such as. do not have interfering substituents,. are suitable solvents for the acidification reaction. The preferred reaction medium, however, is a solution, especially an aqueous solution, of the precursor and the acid. The amount of precursors in the aqueous solution can vary greatly from a small to a larger part of the reaction medium.

Suitable temperatures which are preferred are from 0 to 100°C,

although higher or lower temperatures may be used.

The order of addition of reactants and solvent can be varied to suit the particular reaction conditions desired. For example, the precursor can be added directly to the acid and kept at a controlled temperature for a certain time, then a solvent, such as water, can be added while maintaining the temperature. Alternatively, the precursor can be added to an aqueous solution of an acid. Another method is to slowly add a concentrated acid to the precursor which may be in solution.

Separation of the compound of formula I from the reaction medium can be carried out by direct filtration, preferably after cooling the reaction medium, or by evaporation of the reaction medium. Addition of water promotes the separation, as carboxylic acids are less soluble than their salts. The reaction product can be redissolved and again separated from solution to effect further purification, as from acidic solutions. Alternatively, the product of formula I can be recrystallized from solutions such as aqueous alcohols, e.g. 2-propanol, or from other organic solvents, e.g. a mixture of acetone petroleum ether.

When it is desired to form the O-acetyl derivatives of formula I, the reaction medium may contain a source of acetyl ions, such as acetic anhydride or acetyl halides. Alternatively, after formation of 5-(L|--fluorophenyl)-salicylic acid, this can be treated with a source of acetyl ions to obtain the O-acetyl derivative.

A preferred group of compounds of formula II includes those of the general formula:

where R is hydroxy or oc-hydroperoxy-sec-alkyl., where alkyl is a lower molecular hydrocarbon radical, and M is an alkali metal, such as lithium, sodium or potassium, or a metal such as magnesium, aluminium, zinc, ferro or cupro.

The preferred method in the manufacture of connecting

one of formula I from the precursor compounds of formula III involves acidification of the precursor with glacial acetic acid. or a mineral acid such as sulfuric acid, or combinations thereof. The reaction can be carried out in aqueous solution at temperatures of 0 100°C. in the course of from approx. 30 minutes to a few hours. Recovery of the compounds of formula I can be accomplished by cooling the reaction mixture and filtering it. This can possibly be confirmed by recrystallization from an organic medium such as acetone-petroleum ether. The use of acetic anhydride in the reaction medium is preferred in the preparation of the O-acetyl derivative of formula I.

■ Example'1 -\ below shows appropriate special proce-

ways in the preparation of ^-(-h-fluorophenyl)-salicylic acid and the O-acetyl derivative thereof from ■compounds of the formulas II and III where R is hydroxyl and æ-hydroperoxy-sec-dimethyl, and M -is an alkali metal. Similar methods can be used, as mentioned above. for others therein-

levels of the formulas II and III. For example, when M or R is a Grignard radical, or when M is magnesium, ferro or cupro, the syringe can be carried out by using -of an acid-, as is used for other salts in one aqueous solution, by the above-mentioned temperatures and conditions. When R is -OM, the procedure is essentially just as described for other salts.

The procedures for producing the precursors of the formulas

II and III vary greatly and are illustrated below with several special examples. For example, ortho-halogenation of ^-(%-fluorophenyl)-phenol can be followed by treatment with er, organometallic compounds and carbon dioxide to obtain a metal-b-metallo-5-(^-fluorophenyl)-salicylate. In another method, k-(k-fluorophenyl)-phenol can be treated with. a metal hydroxide and then a metal carbonate in the presence of carbon monoxide or carbon dioxide to obtain a metal 5-(<1>+-fluorophenyl)-salicylate. In yet another method, ^-(^-fluorophenyl)-phenol is reacted with carbon dioxide in the presence of a Friedel-Grafts catalyst y such as AlCl^, ZnCl2,

FeCl^ or BF^. This is a particularly useful way of obtaining aluminum salts of formulas II and III. An alternative approach is to

heating the ^--(^-fluoro enyl)-phenol in an atmosphere of anhydrous carbon dioxide with a metal carbonate to obtain the metal 5-(1+-fluoro eny])-salicylate. The precursor can also be produced by treating a

^-halo-V-fluorobiphenyl with a metal phosphate and water in an atmosphere of carbon dioxide to form the metal (^-f^-fluorophenyl)-salicylates.

In the latter" reaction, ^-halogen-^'-fluoro-biphenyl is first hydrolyzed with water and metal phosphate which also acts as a base to form "i-C^'-fluorenyl)-phenol which is then transferred by reaction with carbon dioxide and metal phosphates . to the desired metal 5-('+-fluorophenyl)-salicylates. If the carbon dioxide in the latter reaction is sloyed, ^-(^t-<1->fluorophenyl)-phenol or its alkali salt, which compound itself is, will be formed. an important starting material.

Other bases which can be used in the production of +-(!)-'-fluorophenyl)-phenol are "alkali metal hydroxides or alkaline earth metal oxides or hydroxides, such as sodium or potassium hydroxide, calcium oxide or barium hydroxide, the reaction not being limited to the use of a metal phosphate if one wishes to prepare h-(h'-fluorophenyl)-phenol Favorable temperature ranges for the reaction in the preparation of k-(h'-fluorophenyl)-phenol are from about 225°C to 350°C.

Furthermore, in addition to using ^-halogen-^<1->fluorobiphenyl as starting material in the production of -fluorenyl)-phenol, you can use compounds which in the ^-position instead of halogen, have such groups as sulfo , sulfino, halosulfonyl or phosphono.

When R as indicated above is a-α-hydroperoxy compound, the precursor can be prepared by coupling a fluorobenzene and a 2-sec-lower alkyl-5-aminobenzoic acid followed by oxidation with oxygen in the presence of a metal carbonate to form, a metal 2-(α-hydroperoxy-sec-alkyl)-5-C^-fluorophenyl)-.salicylate.- Various α-hydroperoxy compounds can be obtained by. to vary the 2-secondary substituents on the 5-aminobenzoic acid. ; Likewise, fluorobenzene can be lobulated with a 3-aminobenzoic acid followed by treatment with a metal carbonate in the presence of oxygen to obtain a metal 5-(1+-fluorophenyl)-salicylate. This method is of particular value in the preparation of ng of the cwpro-{)+-fluorophenyl)-salicylate. ','■-.'' -..-.'•'

The method compounds can be used to treat inflammation by reducing the inflammation and relieving the pain in such diseases as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and. "rheumatic" fever'. The present-method compounds also have better potency at the same dosage than similar, previously known compounds and exhibit fewer side effects.

The process compounds also have antipyretic and analgesic activity, and are used in the same way and in the same doses as when they are used in the treatment of inflammation as discussed below.

In addition to a strong anti-inflammatory effect, the process compounds exhibit a lower occurrence of vomiting (emesis effect) than similar, previously known compounds do, especially compounds of the acetylsalicylic acid type ("Aspirin"). The process compounds have a better therapeutic ratio than "Aspirin".

The treatment of inflammation is carried out by oral administration to patients of the method compounds, in a non-toxic pharmaceutically acceptable carrier, preferably in the form of tablets or capsules. The process compounds are used, in an amount from 1 mg to 1^0 mg/kg body weight per day, preferably from approx. 2 mg to approx. 70 mg per kg body weight per day and especially from *+ mg to 10 mg/kg body weight per day. The fastest and most effective anti-inflammatory effect is achieved by oral administration of a daily dose of from approx. U to 10 mg/kg per day. However, the doses must of course be adjusted according to the doctor's wishes. Forsbksmethoden-wood. which the anti-inflammatory activity is determined by the ability of the compounds to inhibit the dropsy caused by the injection of an inflammatory (phlogistic) agent into the tissue in the foot of the rat. Groups of 6 male rats - (Sprague Dawley breed, 150 - 15 -g) -are orally given the compounds to be tested ltime for 0.1 ml. of a l#-ig suspension of carrageenin is injected into the sole surface of the right hind leg. Immediately, and again 3 hours later, the volume of the foot is measured by its displacement of quick blood, and. this is registered -automatically. The difference between the first and final volume is a measure of the hydrosol produced.

The experimental compounds were suspended, or dissolved in 0.5 µg "Methocel", while the control animals received only "Methocel". A usual trial with 30 mg/kg and a repetition plus a dose of 90 mg/kg was usually given.

The above experimental method is known to correlate with the anti-inflammatory activity in humans and is a standard test used to determine anti-inflammatory activity. - This correlation is shown by compounds known to be clinically active, including "Indocin", "Aspirin", "Butazolidine", "Tandearil", "Cortone", "Hydrocortone" and "Decadron". has been compared with similar experiments on the closest of the previously known compounds that have been found, namely 5-phenylsalicylic acid and the corresponding derivatives thereof described in U.S. Patents 2..7M+.916 and 3.123.5^+3, and acetyl-salicylic acid ("Aspirin"). The results of these trials are as follows:

From the above data it appears that '2-hydroxy-5-phenylbenzoic acid given in a dose of 90 mg/kg corresponds approximately to the effect of 2-hydroxy-5-C^'-fluorophenyl)-benzoic acid in less than 1/3 of this dose . In general, it will be seen that the process compounds are stronger at lower doses than the previously known compounds.

In addition to the above experiments, the potency of the process compounds relative to the best known compound, 5-phenylsalicylic acid, was recently determined in rat foot edema experiments as part of a multiplex assay. Three graded doses of each compound were administered. orally to individual groups of 6 rats. All rats were given an intraplantar injection of carrageenan (0.1 ml of a 1% suspension in the upper hindquarters) approx. 1 hour after they received the experimental compounds... 3 hours later the volume of the dropsy foot was measured. a quick solv displacement method. This f or soxrnetode is. corresponding to the one previously described.

The determination was repeated four times as one of the purposes of the experiment was to study the variation from day to day in determinations of relative strength. For 2-acetoxy-5-(1+'-fluorophenyl)-benzoic acid, the four determinations of relative strength varied from V.97 to 8.13, a ratio of 1.6 from highest to lowest-. 2-hydroxy-5-(^' -^fluorophenyl)-benzoic acid ranged from .5.2-0 to 8.56, a ratio of 1.6 as for 2-acetoxy-5-(1+' -fluorophenyl)- benzoic acid.. However, these numbers ■do not differ significantly from a ratio of 1.0, which shows that the trials were "homogeneous within -the limits of trial error.

Table I shows the average foot volume for each of the compounds. The calculations of relative strength and 95$ confidence limits

< calculated below. application of Dunnett's:t) is indicated in Table II.

The combined calculations--of- relative, strength" (ie trial 1 - h)

is also shown in this table. All experiments showed valid results (ie they were linear and parallel)-

The following examples will illustrate the invention - further..

Example 1 - h shows the synthesis of compounds of the formulas II and III to compounds of the formula I. Examples 5-10 show methods for the preparation of the compounds of the formulas II and III.

Example 1

One mole (270.3 g) of potassium 5-C+-fluorophenyl)-salicylate was dissolved in 1.2 L of glacial acetic acid at 85-90°C. Sufficient tetrasodium ethylenediamine tetraacetate was added to remove the color due to heavy metal ions. 3.6 1 of water was added over the course of 30 minutes at 85 - 90°C. After cooling, 5-C-f-fluorophenyl)-salicylic acid was filtered off and dried. The yield was 218 - 227 g (9^ - 98$)', and the melting point was 20<!>+ - 205°C.

The lithium, sodium, rubidium and cesium 5-(i+-fluorenyl) salicylates were acidified in the same way.

Example 2

One mole of carium-2^[2-(hydro:ro.peroxy3-prop.yl]-5-<1+-fluorophenyl)-benzbate was heated to 85 - 90°C in % 1 56$-ig aqueous, -acetic acid containing <>>+00 ml of concentrated sulfuric acid. This temperature was maintained for 1 hour. The mixture was diluted with <l>f:'T water and then cooled, whereby a 95% yield of 5-C^-fluorophenyl)-salicylic acid was obtained after filtration and washing, the melting point was 203 - 205°C.

Example 3

100 g (0.37 mol) of potassium 5-(^-fluorophenyl)-salicylate was suspended in 300 ml of acetic anhydride. The suspension was cooled to 10-15°C and 13 ml (0.2*+ mol, 2<*>+ g) of concentrated sulfuric acid was added. The mixture was stirred for a short time. 2.06 1 of water was added carefully and .acetyl-^-^-fluorenyl)-salicylic acid from Utrert. ' The melting point was 138 - 1<L>(-0°C. Recrystallization from acetone petroleum ether raised the melting point to 1^3 - 1^5<0>C.

The lithium, sodium, rubidium and esium 5-(^-fluorenyl) salicylates were acidified. identical way by which one gave O-acetyl-5-(U-fluorophenyl)-s:alicylic acid.

. Example, h

One mole (328.37 g) of potassium 2-[.2-(hydroperoxy.)-propyl]-5-(^-fluorophenyl)-benzoate was suspended in 1.6 L (17.mol) of acetic anhydride, followed by the addition of 37.2 ml (68.!+ g, 0.68^ mol) of concentrated sulfuric acid.in the course of 1G minutes. The mixture was heated to 80°C for 15 minutes, and then cooled to room temperature. 11.2 L of water was added to the reaction mixture over the course of one hour, with the first 306 mL (17 moles) being added over the course of 30 minutes. When the addition of the water was finished, the product was filtered and dried. The yield was 263 g ($96) and the melting point 137 - 1<1>+0°C. Recrystallization from acetone petroleum ether. raised the melting point to .Pi3 - l'i5°C..

Example 5

where X is halogen (F, Cl, Br, J), and

M is an alkali metal or magnesium halide, MgX.

^--(^--fluorophenyl)-phenol can be halogenated directly or via nitration, reduction and a Schiemann or Sandmeyer halogenation at the 2-position to form a 2-halo-l+-(Lt- -f luorf enyl)-f enol. The 2-halo-1+-('+-fluorophenyl)'-phenol is treated with an organometallic compound consisting of an organic radical and an alkali metal or with a Grignard organomagnesium halide followed by anhydrous carbon dioxide to obtain a metal-0-metallo- 5-(^—f luorf enyl)-salieylate.

■ . Example . 5a Preparation of 2-bromo-^-(i+-fluorenyl)-phenol

A mol (188 g) of ^-(^--fluorophenyl)-phenol is suspended in 1 liter of methylene chloride and treated at 0°C with 0.95 mol of bromine. The solids are filtered off, washed and dried, whereby 2-bromo-1+-(!+-fluorophenyl)-phenol is obtained.

Example 5b

Preparation of lithium-0-lithio-5-(^-fluoro-phenyl)- salieylate from 2-bromo-M-(^+- fluoro-phenyl)-phenol

One mole (267.10 g) of 2-bromo-1f-(i+-fluorophenyl)-phenol was placed

in 6.0 L anhydrous tetrahydrofuran and cooled to -75°C. 2 mol • n-butyllithium in ether was added, and the mixture was stirred at

-75°C for 5 hours. 500 g of anhydrous powdered ice was added and the mixture was stirred and allowed to warm to room temperature.

tur.. The impure lithium-0-lithio-5-(!+-fluorophenyl)-salieylate was filtered off and dried in vacuo.

Example 6

where M is an alkali metal.

^-(if-fluorenyl)-phenol can be treated with an alkali metal hydroxide to form the corresponding anhydrous alkali metal-*+-(V-fluoroenyl)-phenoxide. The latter compound gives, on treatment with an alkali metal carbonate in the presence of carbon monoxide or carbon dioxide, the desired alkali metal (C^-fluorenyl)-salieylate.

Example . 6a

Preparation of alkali metal (^-- fluorophenyl)- phenoxides

-■'v - " ' '■ where M is an .alkali metal.

A' mol. ^-(^f-Fluorophenylj-phenol and one mole of the appropriate alkali metal hydroxide were placed in 1 liter of 75% aqueous methanol and heated under reflux and stirring in a nitrogen atmosphere for 2 hours. After cooling, the water and methanol were removed in vacuo, and the remaining alkali metal 1+-(1+-fluorophenyl)-phenoxide was heated in vacuo at 110° C. for 18 hours. The yield of anhydrous product was quantitative.

Any alkali metal hydroxide is suitable to form the corresponding .(M-C^-fluorophenyl)-phenoxide. These include lithium, sodium, potassium, rubidium and cesium hydroxide.

Example 6b'

Preparation of alkali metal 5-(^-fluorophenyl)-salicylates using carbon monoxide from alkali phenoxides

where M is an alkali metal.

Alkali metal ^-C^-fluorophenyl)-phenoxides are treated with carbon monoxide and the appropriate alkali metal carbonate using the procedure for the preparation of potassium 5-C1!-fluorenyl)-salieylate. The dividend is equivalent.

Example 6e

Manufacturing ; of alkali metal 5-(1+-fluorophenyl)-salicylates from alkali phenoxides using carbon dioxide

where M is an alkali metal.

One mole of the appropriate alkali metal (^-C+-fluorophenyl)-phenoxide is placed in an autoclave intended for continuous milling of the solids, and then a pressure of dry carbon dioxide of 56.3 kg/cm<2> is applied

overpressure. The internal temperature was raised to 130 - 1<i>f5°C and held in this range for h hours, while the solids were subjected to continuous grinding. The temperature was then raised to 220 - 2h0°C for a further k hours. The autoclave was cooled <p>g the solids

slurried in 2 liters of acetone for 1 hour. The salicylate salt was filtered off and dried. The yield was 85 - 95$ depending on the alkali metal cation used.

Example 7

where M is an alkali metal.

^-(^-Fluorophenyl)-phenol was heated in an atmosphere of anhydrous carbon monoxide and/or carbon dioxide with an alkali metal carbonate whereby one obtained an alkali metal (J-C^-fluorophenyl)-salietylate. Particularly advantageous was the use of potassium bicarbonate, potassium carbonate, rubidium carbonate and/or cesium carbonate.

Example 7a

Preparation of potassium 5-C+-fluorophenyl)-salieylate from h-(^-fluorophenyl)-phenol with carbon dioxide

100 g of finely ground ^-(^--fluorenyl)-phenol and 300 g of powdered anhydrous potassium carbonate were intimately mixed. This mixture was placed in an autoclave and placed under a dry carbon dioxide pressure of 56.3 kg/cm 2 . The autoclave was heated at 235 - 2<1>+5°C for 6 hours and then cooled to 25°C. The pressure was then lifted. The solid reaction products were finely ground and slurried for 1 hour in 1.5 liters of water. The solids were filtered off, reslurried with 800 ml of acetone and filtered again. The filter cake was dried, giving a 95$ (117 g) yield of potassium 5-(^-fluorophenyl)-salieylate contaminated with traces of potassium carbonate and ^-(^-fluorophenyl)-phenol.

Potassium bicarbonate, rubidium carbonate and cesium carbonate can be used instead: potassium carbonate and give similar results. Sodium bicarbonate gives reduced yields. Sodium carbonate, magnesium carbonate and calcium carbonate give lower yields of 5-(^-fluorophenyl)-salieylate.

Example 7 b Preparation of. potassium-S^C1!— f luorf enyl-)-salieylate from

^-(V-fluoro enyl)-phenol' with carbon monoxide.

^-(^-Fluorophenyl)-phenol is converted to alkali metal 5-(Lt--fluorophenyl)-salicylates using carbon monoxide instead of carbon dioxide, in the presence of a threefold excess by weight of the appropriate alkali metal carbonates. The process details are identical to those in the previous example when carbon dioxide is used.

Example 8

where X is -chlorine, bromine or iodine, and M is an alkali metal.

^-halogen-V -fluorobiphenyls are heated with alkali phosphate.er and

water in a car bondioxydatmo sphere-, giving -alkali metal-5-C^-fluorophenyl)-salicylates.

Example' 8a

Preparation of sodium 5-(1+-fluorophenyl)- salieylate

One mole (251.1 g) of 3-bromo-3'-fluorobiphenyl was placed in 1 liter of water containing 500 g (1.96 mol) of disodium hydrogen phosphate heptahydrate. The mixture was placed in an autoclave with agitation under 56.3 kg/cm 2 carbon dioxide pressure. The mixture was heated to 330°C for 18 hours, cooled, the solids filtered off and dried. The solids contained sodium 5-(1+-fluorophenyl)-salieylate as shown by thin layer chromatography on "Silica Gel G'" using 90 benzene-25-dioxane-<1>+-acetic acid. The impure salt was used without further purification.

By following the above procedure, but by omitting the use of carbon dioxide under pressure, -fluorophenyl)-phenol was obtained.

Example 9

-where R and M are- as indicated .for ■ formula IT.

A 2-secondary-aryl-5-aminobenzoic acid can be coupled with fluorobenzene in a Gomberg-type reaction, giving a 2-secondary-alkyl-5-O+-fluorophenyl)benzoic acid. The latter compound is oxidized with oxygen in the presence of an alkali metal carbonate, whereby an alkali metal 2-(α-hydroperoxy-sec-alkyl)-5-(i+-fluorophenyl)-salieylate is obtained.

Example 9a Preparation of potassium 2-[2-(hydroperoxy)-propyl]-5-(i+-fluorophenyl)-benzoate

A mixture of 0.1 mole of 2-isopropyl-5-aminobenzoic acid, 200 ml of fluorobenzene and 9.0 g of isoamyl nitrite was heated on a steam bath until a vigorous evolution of gas began. This development was allowed.

to continue without heating Until it- stopped. The mixture was so. heated on a steam bath for 3 hours. The excess fluorobenzene was removed in vacuo and the residue separated chromatographically on silica gel using a mixture of 90 parts -benzene- 25 parts dioxane-h parts "acetic acid, which gave 2-isopropyl)-5-C+-fluorophenyl)-benzoic acid .

One mole (258.3 g) of 2-iso<p>ro<p>yl-5-(1f-fluorophenyl)-benzoic acid was placed in 3.9 l of water containing 800 g of potassium carbonate. The mixture was heated to 90-95°C for 3 hours in an oxygen atmosphere with vigorous stirring. The mixture was cooled, yielding 2x6 g (85%) of potassium 2-[2-(hydroperoxy)-propyl]-5-(1+-fluorophenyl)-benzoate.

Example 10

3-Aminobenzoic acid was coupled with fluorobenzene by a Gomberg-type reaction to give 3-(^-fluorophenyl)-salicylic acid. This compound gave on treatment with cupricarbonate at high temperatures in the presence of oxygen cupro-5-(^-fluorophenyl)-salieylate.

1

Example 10a

Preparation of 3-(^-fluorophenyl)-benzoes<y>re

One mole of 3-aminobenzoic acid was added to one liter of fluorobenzene.

One mole of isoamyl nitrite was added and the mixture boiled at reflux until the evolution of nitrogen ceased. The excess of fluorobenzene and isoamyl alcohol was removed in vacuo and the residue separated

chromatographically over silica gel by elution with a mixture of 90

parts ben zen-'2 5 parts dioxane-V parts acetic acid, which gave 3-.C<1>*—

■fluorophenyl)-benzoic acid.

Example 10b

' Preparation of cupro-5-C^-fluorophenyl)- salieylate

<*>+0 g of 3-C+-fluorophenyl)-benzoic acid was placed in ^00 ml of diphenyl oxide and the mixture heated to 210°C. ^3.5 g (0.186 mol) of basic cupric carbonate was then added over h0 minutes and the mixture heated for a further 15 minutes at 255 - 260°C. The mixture was cooled, diluted with diethyl ether and filtered, yielding impure cupro-5-C+ -fluorophenyl)-salieylate.

Claims (1)

Analogous procedure for the preparation of new, therapeutically active compounds of the general formula: where A is hydrogen or acetyl, characterized in that a precursor compound of the general formula: • where M is a metal ion or the Grignard radical -MgX, where X is halogen or OR', where R' is alkyl, aryl, alkenyl, alkynyl, aralkyl or acyl, and R is hydroxy, -OM where M is as indicated above, or an α-hydroperoxy group of the general formula: where R" is alkyl, aralkyl or aryl, is reacted with an acid, optionally during simultaneous or subsequent acetylation.