CS196305B2 - Process for preparing derivatives of benzophenones - Google Patents

Abstract

0-Hydroxybenzophenones and derivatives thereof are described together with a process for the their production. The compounds have anti-allergy activity and are characterised by the presence of an alkyl substituent on the hydroxyphenyl ring.

Description

The invention relates to a process for the preparation of novel benzophenone derivatives of the general formula (I) in which R @ ¹ , R @ 2 and R @ ⁵ are each hydrogen or ethyl, at least one of said substituents being ethyl, (X) n being one or two substituents independently selected from chloro, fluoro, methyl, carboxy, -COOR ^5, and trifluoromethyl, Z is hydrogen or · COR ^5, Y is oxygen or NOH · NOCOR5 and R5 is C ^ alikyl or phenyl, denotes when (X) _{n is} one or two chlorine atoms, Y and Z are as defined above, R ² is ethyl and one of R ¹ and R ³ is other than hydrogen, or when (X) n is a chlorine atom in the 4-position, Y and Z are as defined above and R 3 is e>

one of R 1 and R 2 is other than hydrogen and when R 1 is ethyl, R 2 and R 3 are hydrogen and Y and Z are as defined above, (X) n is other than two. chlorine atoms in position

2,4 or 3,4 or a chlorine atom in the 2 or 3 position, a fluorine atom in the 4-position or a methyl in the 3-position.

There is extensive literature on benzophenones, their production and their use. However, hitherto it has not been known that o-hydroxybenzophenones and their derivatives can be used to treat allergic conditions, particularly hypersensitivity diseases such as asthma, in animals, including humans.

The invention therefore also relates to a process for the preparation of pharmaceutical preparations comprising a pharmaceutically acceptable carrier and, as active ingredient, a benzophenone derivative of the formula I.

The benzophenones of the formula I in which Y does not represent an oxygen atom may exist either in the syn-form or in the anti-form; all said isomers and mixtures thereof are included within the scope of the invention.

The most preferred compound of formula (I) is 4‘-chloro-5-ethyl-2-hydroxybenzophenone.

The preparation of the novel benzophenone derivatives of the general formula (I) by the process according to

The invention is that? the compound community? formula II. /

wherein R ¹ , R ² and R ³ are as defined above and Z ¹ is Z or methyl, reacts with a compound of formula III

wherein Q is a hydroxy or halogen atom and (X) _n is as defined above, with heating in the presence of a Lewis acid as a catalyst and in the case where Z ¹ is methyl, followed by hydrolysis in the presence of an acid and then to produce a compound of formula I wherein Y is NOH, the resulting compound is reacted with hydroxylamine in the presence of a base at normal temperature, then, if a compound of formula I wherein Z is COR ⁵ and / or Y is to be obtained is NOCOR ⁵ , acylated with previously obtained compounds of formula I wherein Z is hydrogen and / or Y ^is NOH, with a compound of formula R ⁵ COQ, wherein Q is a chlorine atom or a group of formula (R ⁵ COJ wherein R ⁵ It is as hereinbefore defined, at room temperature to the boiling point of the reaction mixture, that aluminum halide is preferably used as the Lewis acid.

When X is a halogen atom, the reaction may be carried out, as mentioned above, in the presence of a Lewis acid, such as an aluminum halide such as chloride, as a catalyst, in a suitable inert solvent such as 1,1,2,2-tetrachloromethane or carbon disulfide .

Reducing the amount of undesired isomer or undesired isomers can be achieved by appropriately selecting the reaction conditions. Especially important is the control of the reaction temperature; the ideal reaction temperature is from 20 ° C to the boiling point of the reaction mixture, preferably from 80 ° C to the boiling point of the mixture.

The derivatives of formula (I) have significant antiallergic activity in one or more of the four assays generally used to detect anti-analgesic activity. Two of these tests are in vitro doughs - tests for cut guinea pig or human lung tissue - and consist of direct measurement of mediators, histamine and slow responder (SRS-A) at anaphylaxis; SRS-A has been shown to be released by asthmatic human lungs. Test benzophenones of formula I were considered to be effective if, in the above-described guinea pig lung tissue assay, a dose of 10 µg / ml or less than at least 30 (%) of SRg-A release inhibition was achieved. the lung tissue at said dose corresponds, depending on the absorption, distribution and metabolism of the test substance, to an in vivo dose ranging from 0.5 to about 100 mg / kg for oral administration.

The other two tests used are in vivo tests - the Herxheimer test and the peritoneal anaphylaxis test in rats - and express the activity of the compounds in two different animal species when administered orally. In the Herxheimer test, sensitized guinea pigs are protected by test substances from bronchospasm (bronchial muscle spasm) induced by antigen aerosol, and in the rat abdominal erythylaxis test, the level of SRS-A released after irritation is directly measured. those which are effective at doses of 300 mg / kg or less.

The benzophenones and their derivatives of formula (I) exhibit activity in one or more of the above tests (the broadest spectrum being those which exhibit antiallergic activity in all four tests) and can therefore be used in the prophylaxis and therapy of hypersensitivity diseases, including asthma In some cases, the compounds of formula (I) may be used in diseases in which excess prositaglandins are released, as well as respiratory stimulators, and the compounds of formula (I) have low toxicity.

The benzophenones of formula (I) or therapeutics containing said agents can be administered by various routes and can be formulated for this purpose in various dosage forms. Said substances or preparations may be administered orally, rectally, locally, parenterally, for example by injection and continuous or intermittent intraarterial infusion, for example in the form of tablets, lozenges, sublingual tablets, sachets, capsules, elixirs, suspensions, aerosols, ointments, e.g. up to 10% (w / w) of the active ingredient in a suitable substrate, in the form of soft and hard gelatine capsules, suppositories, injectable solutions and suspensions in a physiologically acceptable environment and sterile packed powders adsorbed to a suitable carrier for injection solutions. Particularly suitable are therapeutic preparations in unit dosage form, each unit dose containing preferably 5 to 500 mg of a compound of formula I (5.0 to 50 mg for parente196305 for oral administration, 5.0 to 50 mg for inhalation and 25 to 500 mg). mg for oral or rectal administration).

As indicated in the above tests, doses ranging from 0.5 to 500 mg of active ingredient per kg of body weight per day, preferably 0.5 to 20 mg / kg per day, can be administered. However, it is readily understood that the amount of the compound or compounds of Formula I that can actually be administered must be determined by the physician based on all relevant circumstances, such as the type of disease to be treated, the compound to be administered and the route of administration chosen. formulation, and therefore the above dosage range is not intended to limit the scope of the invention in any way.

In the specification, the term "unit dosage form" refers to a physically discrete dosage unit containing an individual amount of active ingredient, usually in admixture with a pharmaceutically acceptable diluent, or in association with a pharmaceutically acceptable carrier, wherein the amount of active ingredient is such that therapeutic administration is required in one or more units, or, in the case of divisible units such as scored tablets, at least one portion, such as half or quarter, of a discrete unit is required for one therapeutic administration.

The therapeutic compositions of the invention normally comprise at least one compound of Formula I and a pharmaceutically acceptable carrier; the active ingredient is either mixed with or dissolved in the carrier, or enclosed or encapsulated in a digestible carrier, which may take the form of a capsule, sachet, capsule, paper wrapper or other container, or filled in a suitable container such as an ampoule . As carriers or diluents, a solid, semi-solid, or liquid material may be used as a vehicle, excipient or medium for the therapeutically active agent.

Suitable diluents or carriers include, for example, lactose, glucose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, anhydrous silica, microcrystalline cellulose, calcium silicate, silica gel, polyvinylpyrrolidine, polyvinylpyrrolidine starch, modified starches, gum arabic, calcium phosphate, cocoa butter, ethoxylated esters, cocoa oil, peanut oil, alginates, gum tragacanth, gelatin according to BP, methylcellulose, polyoxyethylene sorbitol monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate , sorbitol and oleyl alcohol sesquioleate, and propellants such as chlorofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a glidant may be added to prevent sticking and joining of the sprayed components in the embossing nut and the punch of the tabletting machine. Aluminum, magnesium or calcium stearate, talc or mineral oil may be used for this purpose.

The invention is illustrated by the following examples.

Examples

Example 1

4‘-Chloro-5-ethyl-2-hydroxybenzophenone

To a solution of 4-ethylphenol (122.1 g) and 4-chlorobenzoyl chloride (140 mL) in anhydrous 1,1,2,2-tert-chloroethane (800 mL). aluminum chloride (267 g) was added portionwise with stirring over 30 minutes. The mixture was heated to 105 ° C with stirring for 22 hours and then a mixture of ice (600 g) with concentrated hydrochloric acid was slowly added with cooling, with vigorous reaction. The organic layer was separated, the aqueous portion was shaken twice with chloroform (200 mL each), the organics were combined and the solvents were distilled off. A dark oily residue is obtained which, under reduced pressure distillation, yields two main fractions: B (17.4 g) at 150-160 ° C at 0.3 torr, and C (110.8 g) at 160-168. ° C at 0.3 torr.

The title compound is obtained by cooling the distillate to -20 ° C and recrystallizing the crystallized product from n-hexane at 0 ° C. It forms a yellow crystalline solid, m.p. 35-38 ° C.

For C15H13ClO2 calculated:

69.1% C, 5.0% H, 13.6% Cl;

found:

69.0% C, 5.0% H, 13.9% Cl.

Example 2

4‘-Chloro-5-ethyl-2-hydroxybenzophenone oxime

To a mixture of 4'-chloro-5-ethyl-2-hydroxybenzophenone (65.2 g), potassium hydroxide (170 grams), water (700 mL) and ethanol (150 mL) was added hydroxylamine hydrochloride (70, 0 g) and the mixture is stirred at room temperature for 18 hours: during this time, all the pastry material has gone into solution. The solution was acidified with 5 N hydrochloric acid, shaken with ether (3 x 200 mL), the combined ether extracts were washed with 10% aqueous sodium carbonate (2 x 200 mL), and the solvent was distilled off. The almost colorless residue was recrystallized from benzene / petroleum ether (b.p. 60-80 ° C) 4: 6 to give a colorless crystalline solid (29.9 g) and a second crop (14.5 g). Melting point 117 ° C.

1,8305

For C 15 H 14 ClNO 2 calculated:

65.3% C, 5.1% H, N 5.1%, 12.9% Cl;

loaded*

H, 4.9; N, 5.1; Cl, 12.9. (Stereoisomer of the same kind as in Example 1a.

Example 3

4-Ethyl-4‘-fluoro-2-hydroxy benzophenone

Starting from 3-ethylphenol (24.4 g) and 4-fluorobenzoyl chloride (34.9 g) as described in Example 2, a crude product is obtained which yields three main fractions under vacuum distillation: ((11.4 g), t 126 to 129 ° C at 0.07 torr, C (7.9 g) at 129 to 132 ° C at 0.06 tor, and D (5.9 g) at 132 to 150 ° C at 0.06 tor, all fractions contain about 80% of the desired isomer.

A portion of fraction V (4.0 g) gave, after thin layer chromatography, 2.6 g of the title compound, mp 44-48 ° C.

Example 4

Oxlm of 4-ethyl-4--fluoro-2-hydroxybenzophenone

Reaction of 4-ethyl-4'-fluoro-2-hydroxybenzophenone (21.0 g, 80% purity) with ihydroxylamime hydrochloride (24.0 g) as described in Example 3 affords the title compound after recrystallization from benzene. m.p. 130 DEG-132 DEG C. as a white crystalline solid (10.7 g).

For C15H14FNO2 calculated:

69.5% C, 5.4% H, 5.4% N, 7.3% F; found:

69.2% C, 5.5% H, 5.2% N, 7.2% F.

Example 1 a d 5

2‘, 4‘-Dichloro-3-ethyl-2-hydroxybenzophenone

To a solution of 2-ethylphenol (12.2 g) and 2,4-dichlorobenzoyl chloride (23.1 g) in 1,1,2,2-tetrachloroethane (100 mL) was added portionwise with aluminum chloride (26, 7 g) and the mixture is heated under reflux for 21 hours. After cooling, the solution is poured into concentrated hydrochloric acid (100 ml) and ice (200 g), the organic layer is separated, the aqueous layer is washed twice with chloroform, the combined organics are washed twice with 10% aqueous sodium carbonate solution, dried with monohydrate magnesium sulfate and solvents were distilled off. The dark, viscous oily residue obtained (30.0 g), after distillation under reduced pressure, yields a main fraction of 156 DEG-172 DEG C. at 0.06 torr containing 85% of the desired product; with ferric chloride gives a purple-red color indicating the presence of o-hydroxyketone. The crude product was purified by column chromatography on silica gel with benzophenone of? ²² = 1.6163.

Example 6

4-Ethyl-3‘-fluoro-2-hydroxy benzophenone

Prepared from 3-ethylphenol (12.2 g), 3-fluorobenzoyl chloride (17.5 g) and aluminum chloride (26.7 g) in 1,1,2,2-tetrachloroethane (75 mL) in the same manner, as described in Example 3, but heating the reaction mixture to reflux, not to 105 ° C. The product was purified by silica gel column chromatography; tt between 0 ° C to 20 ° C, По ^й = 1.5962.

Example 7

To a solution of 4-ethylphenol (0.86 g, 0.0070 mol) in 2.5 N aqueous sodium hydroxide solution (5.6 mL) was added dropwise 4-chlorobenzoyl chloride (1.35 g, 0.0077 mol) and the reaction mixture shake vigorously for 15 minutes; A light brown solid precipitated. The mixture was diluted with water (10 mL), the precipitate was filtered off, washed with water (3 x 20 mL) and dried. Recrystallization of the product from n-hexane twice gave a light brown crystalline 4-ethylphenyl ester of 4-chlorobenzoic acid, mp 66.5-67 ° C.

The latter ester (2.6 g) was heated to 125 ° C with aluminum chloride (1.33 g) in carbon tetrachloride for 6 hours. At the end of the reaction time, a sample of the mixture was taken, quenched with dilute hydrochloric acid, and the organics were extracted into chloroform. Analysis of the chloroform extract by gas chromatography did not reveal the starting ester, and by comparison with an authentic sample it was found that 4‘-chloro-5-ethyl-2-hydroxybenzophenone was formed.

In the same way prepare:

5-ethyl-2-hydroxy-4'-methylbenzophenone, m.p.

to 51 ° C, and 4‘-chloro-3,5-diethyl-2-hydroxybenzophenone, m.p.

v. 188 ° C at 1.4 torr.

Example 8

2-Benzoyloxy-5-ethyl-4'-chlorobenzophenone

To a solution of 2-hydroxy-5-ethyl-4'-chlorobenzophenone (5 g, 0.019 mol) in a solution of sodium hydroxide (7.5 g, 0.187 mol) in water (75 ml) was added dropwise benzoyl chloride over 5 minutes with vigorous stirring; the temperature rises to about 50 ° C. The mixture was stirred further

196303

1.5 hours at room temperature, then shaken with ether, washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate, the desiccant is filtered off and the solvent is distilled off. The residue is recrystallized from n-hexane to give colorless crystals of the desired product, mp 79-81 ° C.

Example 9

2-Acetoxy-4'-chloro-5-ethylbenzophenone

2-Hydroxy-5-ethyl-4'-chlorobenzophenone (3 grams) was added to a mixture of acetic anhydride (10 mL) and acetic acid (1 mL) and the mixture was heated under reflux for 3.5 hours. After cooling, the solution is poured into dilute sodium hydroxide solution, the product is taken up in chloroform, the chloroform solution is washed with 10% sodium bicarbonate solution (50 ml), dried over magnesium sulfate and the solvent is distilled off. The oily residue obtained after distillation under reduced pressure yielded the desired product (2.3 g), m.p. 160-165 ° C at 3.5 rt.

Example 10

5-Ethyl-2-hydroxy-4'-trifluoromethyl-benzophenone

Aluminum dichloride (0.6 g, 0.004 mol) was added to dichloromethane (2 mL) and 4-trifluoromethylbenzoyl chloride (1 g, 0.0048 mol) was added with stirring followed by 4-ethylanisole (0, 6 g, 0.0044 mol) in dichloromethane (1 mL). The mixture was stirred overnight at room temperature, then poured into a mixture of ice and concentrated hydrochloric acid and the product was shaken into chloroform. The chloroform extract was washed with 10% sodium bicarbonate solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. There was thus obtained 4-ethyl-2-methoxy-4orm-trifluoromethylbenzophenone (1.2 g) as a yellow oil.

The product was then heated to 110-120 ° C with 55% aqueous hydrobromic acid (27.5 mL) for 5 hours. The reaction mixture gave the desired product after evaporation to dryness.

Example 11

5-Ethyl-2-hydroxy-3‘-carboxy- and 3‘-methoxycarbonylbenzophenone

Aluminum chloride (39.9 g, 0.3 mol) was added with stirring to dichloromethane (133 mL), and 3-methoxycarbonylbenzoyl chloride (59.5 g, 0.3 mL) was first added to the mixture with ice-cooling and stirring for half an hour. mol) followed by a solution of 4-ethylanisole (40.8 g, 0.3 mol) in dichloromethane (70 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was worked up as described in Example 15 to give 5-ethyl-2-methoxy-3‘-methoxycarbonylbenzophenone.

The latter compound was heated to 110-120 ° C with 55% aqueous hydrobromic acid (500 mL) for 5 hours. After evaporation to dryness, the reaction mixture yields 5-ethyl-2-hydroxy-3on-carboxybenzophenone, which has the corresponding elemental analysis (S, H and N).

The latter carboxylic acid was heated at reflux overnight with methanol (500 mL) containing concentrated sulfuric acid (5 mL). The reaction mixture was poured into water (1 L), the solution was shaken with ether, the combined ethereal extracts washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. The desired ester is obtained which has the corresponding elemental microanalysis.

Claims (3)

OBJECT OF THE INVENTION A process for the preparation of novel benzophenone derivatives of formula I (I) (X) _n is one or two substituents independently selected from chloro, fluoro, methyl, carboxy, COOR ⁵ and trifluoromethyl, Z is hydrogen or COR ⁵ , Y is oxygen, NOH or NOCOR ⁵ and R ⁵ is C _1-4 alkyl or phenyl, provided that when (X) _{n is} one or two chlorine atoms, Y and Z are as defined above, R ² is ethyl and one of R ¹ and R ³ is other than hydrogen, or represents where (X) _n a chlorine atom in position 4, Y and Z have the above meanings and R ³ is ethyl, one of R ¹ and R ² is other than hydrogen a represents where R ¹ ethyl, R ² and R ³ are hydrogen and Y and Z are as defined above, (X) _n is other than two chlorine atoms in a position wherein R ^1, R ² and R ³ each represents hydrogen or ethyl, at least one of said substituents being ethyl, 2,4 or 3,4 or a chlorine atom in the 2 or 3 position, a fluorine atom in the 4 position or a methyl in the 3 position, characterized in that the compound of the general formula II (i.e. wherein R ¹ , R ² and R ³ have and Z ¹ is Z or methyl, reacts with a compound of formula III O (II / J wherein Q is hydroxy or halogen and (X) _n is as defined above, with heating in the presence of a Lewis acid catalyst and, when R ¹ is methyl, followed by hydrolysis in the presence of acid and then, in order to produce a compound of formula I wherein Y is NOH, the resulting compound is reacted with hydroxylaimine in the presence of a base at normal temperature, then, if a compound of formula I wherein Z is COR ⁵ is to be recovered and / or Y is NOCOR ⁵ , acylating previously obtained compounds of formula I wherein Z is hydrogen and / or Y is NOH, a compound of formula R ⁵ COQ ¹ wherein Q is chlorine or a group of formula (R ⁵ CO) O wherein R ⁵ is as defined above, at room temperature to the boiling point of the reaction mixture. 2. The process of item 1, for the preparation of the novel benzophenone derivatives of the above general formula I, wherein R ¹ , R ² , R ³ , Z and Y are as defined in item 1 and (X) n represents one or two substituents independently selected wherein said compound is of formula (II) wherein R ¹ , R ² , R ³ and Z ¹ are as defined above. in step 1, reacts with a compound of the above formula III wherein Q is as defined in point 1 and (X) n is as defined above under the conditions set out in point 1. 3. The process of claim 1 wherein the Lewis acid is an aluminum halide.