KR820000135B1 - Process for preparation of ketone derivatives - Google Patents

Abstract

o-Hydroxybenzophenones I [R1,R2,R3 = H, Et, at least one of them is Et; Ar = Cl, F, Me, COOH, substituted Ph; R5 = C4 alkyl, Ph), useful for treating allergic disease, were prepd. by acylation of corresponding oxime (III) which was prepd. by reacting compd. II with hydroxylamine in the presence of base. Thus, 2-hydroxy-5-methyl-4'-chlorobenzophenone was stirred in a water and KOH soln. and hydroxylamineHCl added. acidified with 5N HCl, filtrated, washed, and dried to give 2-hydroxy-5-methyl-4-chlorobenzophenone oxime(m.p. 163≰C).

Description

Method for preparing ketone derivative

The present invention relates to a method for preparing new benzophenones and derivatives thereof useful for treating allergic sulfur.

-하이드록시 벤조페논과 이의 유도체를 알레르기성 질환의 치료에 사용할 수 있다는 것은 알려지지 않았다.There are many literatures on benzophenones and their preparation and use, but so far

It is not known that hydroxy benzophenone and its derivatives can be used for the treatment of allergic diseases.

Therefore, the present invention reacts the compound represented by the following general formula (II) with hydroxylamine in the presence of a base to prepare a refractory oxime represented by the following general formula (III), and then acylates this compound to yield a general formula. (I) provides a method for producing:

Wherein R ¹ , R ² and R ³ represent hydrogen or ethyl, at least one of which is ethyl, and Ar is substituted by 1-3 groups of chlorine, fluorine, methyl, carboxy, COOR ⁵ and trifluoromethyl Is a phenyl group, R ⁵ is C _1-4 alkyl or phenyl, R ¹ is ethyl, and R ² and R ³ are hydrogen, Ar is 2, 4- or 3, 4-dichlorophenyl, 2- or 3-chloro Not phenyl or 4-fluorophenyl.)

The present invention treats mammals suffering from allergic diseases, and especially treats acute hypersensitivity diseases such as asthma in animals including humans. Doses are given to mammals.

Preferred compounds represented by the general formula (I) in the composition of the present invention and the preparation method thereof are as described above R ¹ , R ² and R ³ , Ar is optionally selected from one to three groups selected from chlorine, fluorine or methyl It is a compound which is a substituted phenyl group.

The compounds of the present invention described above are very good compounds, of course, the compounds represented by general formula (I) have the most useful therapeutic effect, that is, the efficacy and nontoxicity of drugs, which have one or more of the following characteristics: It can be seen that.

(A) one of R ¹ , R ² and R ³ is ethyl, and the other R ¹ , R ² , R ³ substitutions are hydrogen

(B) when R ² and R ³ are hydrogen, R ¹ is ethyl;

(C) Ar is a 4-chlorophenyl group

(D) Ar is a 4-fluorophenyl group

(E) Ar is when unsubstituted phenyl.

Most of the compounds represented by general formula (I) are new and form part of the present invention.

These new compounds represent compounds in which R ¹ , R ² and R ³ represent hydrogen or ethyl (at least one ethyl) and Ar is selected from one to three groups selected from chlorine, fluorine, methyl, carboxy, COOR ⁵ and trifluoromethyl Is a substituted phenyl group, R ⁵ is a compound represented by formula (I) which is C _1-4 alkyl or phenyl, wherein

(A) When Ar is phenyl substituted with chlorine only, R ¹ and R ³ are hydrogen and R ² is not ethyl.

(B) If Ar is 4-chlorophenyl, then R ¹ and R ² are hydrogen and R ³ is not ethyl.

(C) If R ¹ is ethyl, then R ² and R ³ are hydrogen and Ar is not 2, 4- or 3, 4-dichlorophenyl, 2- or 3-chlorophenyl or 4-fluorophenyl.

Among the new compounds, compounds wherein Ar is a phenyl group substituted by one to three groups selected from chlorine, fluorine or methyl are preferred.

The compounds may exist in syn and anti forms, and these isomers and mixtures thereof are included within the scope of the present invention.

Illustrating the acylation of Friedel-Crafts means the reaction between compounds of the general formula ArCOX and the following general formula:

(Where Z 'is a protecting group such as hydrogen or methyl)

Half can be represented by the following scheme:

Where X is a halogen atom or hydroxyl.

When X is halogen, the reaction is preferably carried out using a Lewis acid such as an aluminum halide (e.g. chloride) as a catalyst in a suitable inert solvent such as 1, 1, 2, 2-tetrachloroethane or carbon disulfide. .

When X is hydroxyl, preference is given to using boron trifluoride or (CF ₃ CO) ₂ O as a catalyst with or without a suitable solvent.

Z 'is a protecting group, and the protecting group is removed during or after the reaction to form a compound represented by the general formula (I) wherein Z' is hydrogen.

Unnecessary isomers can be reduced by appropriately selecting reaction conditions, and in particular, by achieving good temperature control, the reaction temperature is ideally from 20 ° C. to reflux temperature, preferably from 80 ° C. to reflux temperature.

In a similar manner, benzophenone can be prepared by the following scheme:

Similar reaction conditions are used.

In the case of reacting with a compound of the general formula ArCOX, the following initial reaction product (A) can be obtained and isolated, which can be subjected to a freeze potential using, for example, aluminum chloride, using similar catalytic conditions as described above. have;

Another example of acylation involving A-COOH derivatives is the use of Ar-CN compounds as acylating agents. This modified method is known as the Houben-Fesch reaction as indicated below;

When the protected hydroxy group Z 'is used in the reaction described above, it can be cleaved into HBr, BF ₃ , AlCl ₃ HI and converted to the desired hydroxyl group.

As mentioned above, ketone derivatives, such as oximes, can be effectively prepared by combining a derivative of hydroxyl amine, preferably hydrochloride and a ketone solution, for example an alcoholic solution, in the presence of a base, i.e. sodium hydroxide or potassium hydroxide. .

-하이드록시 또는 옥심기의 아실 유도체의 제조는 여러가지 방법으로 행할 수 있다. 예를들면 염기성 용액(예를들어 피리딘 또는 수산화나트륨 또는 칼륨과 같은 Ⅰa족 수산화물의 수용액)에서

-하이드록시 벤조페는 또는 옥심을 아실화산과 환류시켜서 행할 수 있다.Also as mentioned above

Production of the acyl derivative of the hydroxy or oxime group can be carried out by various methods. For example in a basic solution (for example an aqueous solution of group Ia hydroxides such as pyridine or sodium hydroxide or potassium)

-Hydroxy benzope can also be performed by refluxing an oxime with an acylation acid.

-하이드록시 벤조페논과 이의 유도체는 항-알레르기성 활성을 검출하기 위해 규칙적으로 사용한 네가지 시험 중 하나 또는 그 이상에서 활성을 갖는다는 것을 알 수 있다.Of the present invention

It can be seen that hydroxy benzophenone and its derivatives have activity in one or more of the four tests regularly used to detect anti-allergic activity.

Two of the above tests were in vitro, guinea pigs and humans cut in humans, regulators cut from human feces of asthma, reactants present in histamine and hypersensitivity (SRA-A), Includes direct measurements.

The compound is active if at least 30% inhibition of SRS-A resolution can be inhibited in the guinea pig test, in which the fermentation is carried out at a dose of 10 Mg / ml or less for a compound of the present invention.

Depending on the absorption, distribution, and metabolism of the test drug, the activity of the fecal test cut out at this level represents orally in vivo at a dose of about 0.5-100 mg / kg.

The other two tests reflect two different types of oral activity in the in vivo test—Herxheimer's test and rat peritoneal hypersensitivity test.

The guinea pigs that are sensitive to bronchospasm caused by antigen aerosols are protected in the Hasselsheimer's test, whereas the rat peritoneal hypersensitivity test directly measures the resolved SRS-A at the base. Activity was normally achieved at a dosage of 300 mg / kg or less when the active ingredient was tested in this in vivo test.

Compounds of the present invention exhibit activity in one or more of the aforementioned tests (the broadest spectrum of compounds exhibit anti-allergic activity in all four tests) and are therefore useful for the prevention and treatment of acute hypersensitivity diseases including asthma. It is also useful for reducing asthma. The compounds are also useful for diseases that release excess prostagladins, for diseases that stimulate the respiratory tract, and the compounds are very low in toxicity.

The compounds or compositions of the present invention can be administered in a variety of ways and can be made in a variety of forms for this purpose. Thus, the compounds or compositions may contain 1-10% by weight of the active ingredient in a suitable base, dragees, sublingual tablets, cachets, sachets, elixirs, suspensions, aerosols and ointments and light gelatin capsules. Or discontinuous arteries, orally and rectally or parenterally, for example, by injection, in the form of suppositories, injectables, suspensions of physiologically acceptable media, sterile packaged powder adsorbed on a carrier for making an injection solution Can be administered by infusion.

Furthermore, the composition is in the form of a dosage unit, preferably 5-500 mg of the compound represented by formula (I) (5.0-50 mg for parenteral administration, 5.0-50 mg for inhalation, oral or rectal In case of administration, make up each dosage unit containing 25-500mg).

As indicated in the above-mentioned test, the active ingredient is dosed daily at a dose of 0.5-300 mg / kg, preferably 0.5-20 mg / kg, and the compound or compound represented by formula (I) The amount is determined by the physician in accordance with all appropriate circumstances, including the condition being treated, the choice of compound to be administered, the choice of method of administration and the like.

As used herein, the expression "dosage unit form" is used to mean a physically separated unit containing the amount of the active ingredient mixed with the pharmaceutical diluent or in combination with the pharmaceutical carrier, the amount of the active ingredient is usually used for monotherapy One or more units required for the dosing, where at least one part, such as half or one quarter of the separate units, is used for the monotherapy if it is in a separable unit, such as a labeled tablet. do.

Typically, the compositions of the present invention are sealed with a carrier which is ingested in the form of a capsule, Sachet, Cachet paper or other container together with a pharmaceutically acceptable carrier or diluted with a carrier, It is composed of at least one compound represented by the general formula (I) by mixing with a carrier. The carrier or diluent consists of a solid, semisolid or liquid substance, which is good as the medium or base agent, excipient of the active therapeutic substance.

피., 메틸셀루로즈, 폴리옥시 에틸렌, 솔비탄 모노라우레이트, 젖산에틸, 메틸과 프로필하이드록시 벤조에이트, 솔비탄 트리올리에이트, 솔비탄 세스퀴올리에이트와 올레일 알콜 및 트리클로로모노플루오로메탄, 디클로로디플루오로메탄, 디클로로테트라플루오로에탄과 같은 추진약이 있다.Diluents or carriers that may be used in the pharmaceutical compositions of the present invention include, for example, lactose, glucose, sucrose, sorbitan, mannitol, propylene, glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicic acid dioxide, microcrystalline cellulose, Calcium silicate, silica, polyvinylphyllolidine, vertical stearyl alcohol, starch, mixed starch, gum arabic, calcium phosphate, cocoa butter, ethoxylated ester, gagao oil, peanut oil, alginate, tracant, gelatin, syrup b

P., methylcellulose, polyoxy ethylene, sorbitan monolaurate, ethyl lactate, methyl and propylhydroxy benzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and trichloromonofluoro Propellants such as methane, dichlorodifluoromethane, dichlorotetrafluoroethane.

In the case of tablets, a lubricant may be used to prevent the powder component from entering or adhering to the punch of the die or tablet, for example, aluminum stearate, magnesium or calcium, talc or mineral oil.

An example of the present invention is as follows.

Example 1

2-hydroxy-5-methyl-4'-chlorobenzephenone oxime (syn and anti)

(A) 2-hydroxy-5-methyl-4'-chlorobenzophenone (13.5 g, 0.055 mol) was stirred with potassium hydroxide solution in water (150 mL), and then hydroxylamine hydrochloride (17.4 g, 0.25 mol) Is added while cooling with ice. After stirring at room temperature overnight, 100 ml of water was added and the mixture was acidified with 5N hydrochloric acid to give a grayish white precipitate which was filtered, washed and dried (14.7 g). Recrystallization of the product from benzene yields 2-hydroxy-5-methyl-4-chlorobenzophenone oxime (7 g) with a melting point of 163 ° C (this is a stereoisomer in which the oxime-OH group and 4'-chlorophenyl are in syn position with each other). ).

(B) Repeat the above procedure using 192 g (0.78 mole) of benzophenone used in (A), and precipitate the second and third crystals formed with benzene solution. The second product (31.5 g) is a mixture of the two forms of oxime, whereas the third product (1.9 g) is a stereoisomer where the oxime hydroxyl and 4'-chlorophenyl groups are in anti-positions to each other.

(C) 4'-Chloro-2-hydroxy-5-methyl-benzophenone-oximediacetate

The oxime produced in (A) (26.2 g) is dissolved in warm acetic anhydride (50 mL) and the solid is separated while cooling.

It is filtered off, the filtrate is evaporated to dryness and the residue is determined as ethanol to give diacetate as a second product (melting point 136 ° C.).

Example 2

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

Treatment with hydroxylamine hydrogen chloride (70.0 g) while cooling potassium hydroxide (170 g), 4'-chloro-5-ethyl-2-hydroxy benzophenone (65.2 g) and ethanol (150 mL) in water (700 mL) And the resulting mixture is stirred at saturation temperature for 18 hours. Dissolution occurs at this time.

The solution was acidified with 5N hydrochloric acid and then extracted with ether (3 × 200 mL), the combined ether solutions were washed with 10% aqueous sodium carbonate solution and evaporated to dryness to give a grayish white solid of 40% of this solid. Recrystallization with benzene / 60-80 ° C. petroleum ether gives a white crystalline solid (29.9 g) and a secondary product (14.5 g) (melting point 117 ° C.).

Microanalysis: C ₁₅ H ₁₄ ClNO ₂ Calculated: C 63.3%, H 5.1%, N 5.1%, Cl 12.9%

Found: C 65.3%, H 4.9%, N 5.1%, Cl 12.9%

(Stereoisomer as in Example 1 (A))

4-ethyl-4'-fluoro-2-hydroxybenzophenone-oxime

Melting point when 4-ethyl-4'-fluoro-2-hydroxybenzophenone (21.0 g, purity 80%) was recrystallized from benzene by treatment with hydroxylamine hydrogen chloride (24.0 g) in a manner similar to that of Example 2. This compound is obtained as a white crystalline solid (10.7 g) at 130-2 ° C.

Microanalysis: C ₁₅ H ₁₄ FNO ₂ Calculated: C 69.5%, H 5.4%, N 5.4%, F 7.3%

Found: C 69.2%, H 5.5%, N 5.2%, F 7.2%

Example 4

2-hydroxy-3'-methyl-4'-chlorobenzophenone oxime

7.5 g, 0.03 mole ketone in ethanol (18 mL) was added to potassium hydroxide (20.74 g, 0.3 mole) in solution (85%) in water (85 mL) at 10 ° C. with stirring and the clapogenic solution was solid Stir overnight with hydroxylamine hydrogen chloride (8.5 g, 0.12 mol).

Acidifying the solution with 5N HCl gives a solid. It was filtered, washed with water and stirred for 45 minutes, then treated with 5% Na ₂ CO ₃ solution (30.5 mL) and the unwanted oxime stereoisomers were removed, filtered and washed with 5% Na ₂ CO ₃ solution, followed by alkali Wash with water until liberated.

The dried solid has a melting point of 175-177 ° C. and recrystallization with a 54% benzene-petroleum ether (boiling point 60-80 ° C.) mixture yields an oxime of 5.45 g and melting point of 178 ° C. (bonded isomers).

Microanalysis: C ₁₆ H ₁₄ ClNO ₃ Calculated: C 63.26%, H 4.64%, Cl 11.67%, N 4.6%

Found: C 63.1%, H 4.8%, Cl 11.5%, N 4.77%

Example 5

2-hydroxy-3-methyl-4'-chlorobenzophenone oxime acetate

Acetic anhydride (12 mL) was heated to 60 ° C. and treated with oxime (5.25 g, 0,02 moles) of Example 4, the stirred mixture was heated to 80 ° C. to dissolve oxime and the solution was immediately cooled in an ice bath. Let's do it.

The precipitated solid is filtered off and washed with petroleum ether (Vision 40-60 ° C.) to give acetate having a melting point of 154-156 ° C. of 4.8 g.

Microanalysis: C ₁₆ H ₁₄ ClNO ₃ Calculated: C 63.26%, H 4.64%, Cl 11.67%, N 4.6%

Found: C 63.1%, H 4.86%, Cl 11.5%, N 4.77%

Claims (1)

And reacting the compound represented by the following general formula (II) with hydroxylamine in the presence of a base to produce the corresponding oxime represented by the following general formula (III), and then acylating the compound. Method for preparing a compound represented by the following general formula (I):

Wherein R ¹ , R ² and R ³ represent hydrogen or ethyl, at least one of which is ethyl, and Ar is substituted by 1-3 groups of chlorine, fluorine, methyl, carboxy, COOR ⁵ and trifluoromethyl Is a phenyl group, R ⁵ is C _1-4 alkyl or phenyl, R ¹ is ethyl, and R ² and R ³ are hydrogen, Ar is 2, 4- or 3, 4-dichlorophenyl, 2- or 3-chloro Not phenyl or 4-fluorophenyl.)