KR20000022496A - 4-(4-oxocyclohexil)benzamide as an intermediate of a medicine - Google Patents

Abstract

PURPOSE: Novel 4-(4-oxocyclohexyl)benzamide derivatives is provided which is used as an intermediate in the synthesis of a medicine, and also directly used for the preparation of a medicine. CONSTITUTION: Benzamide derivatives are represented by formula(I), wherein R1 and R2 are each other independently alkyl having carbon number of 1 to 6, or R1 and R2 together form alkylene. Benzamide derivatives and salts thereof are prepared by reacting a compound of formula(II) with a compound of formula(III) or one of salts thereof, and/or treating a base of formula(I) with an acid to convert from the benzamide derivatives to one of salts thereof.

Description

4- (4-oxocyclohexyl) benzamide as an intermediate product of the drug

The present invention relates to benzamides of the formula (I) and salts thereof:

Where

R ¹ and R ² are independently of each other alkyl having 1 to 6 carbon atoms, or R ¹ and R ² together form an alkylene.

Although the present invention can be used as an intermediate in the synthesis of a medicament, the object is to find a novel compound that can also be used directly in the manufacture of a medicament.

Compounds of formula (I) and salts thereof have been found to be important intermediates in the manufacture of pharmaceuticals.

The present invention provides benzamide derivatives of formula I and salts thereof.

In the present application, the radicals R ¹ and R ² are as defined in formulas I to III unless stated otherwise.

In the above formula, alkyl is preferably unbranched, has 1 to 6 carbon atoms, preferably has 1 to 5 carbon atoms, preferably methyl, ethyl or propyl, alternatively isopropyl, butyl, Isobutyl, secondary butyl or tertiary butyl and n-pentyl, neopentyl or isopentyl.

Alkylene is for example methylene, or preferably ethylene, propylene, butylene or pentylene.

The present invention also relates to a process for preparing benzamide of formula (I) and salts thereof according to claim 1, wherein the compound of formula (II) is reacted with a compound of formula (III) or one of its salts and / or a base of It is characterized by the conversion to one of its salts by treatment:

HNR ¹ R ²

Where

L is Cl, Br, OH or a reactive esterified OH group,

R ¹ and R ² are as defined above.

In addition, the compounds of formula (I) and starting materials used for their preparation are known and are known in the literature under reaction conditions suitable for such reactions (eg, as described by Houben-Weyl in Methods of Organic). Chemistry, Georg-Thieme-Verlag, Stuttgart, etc.). It is also possible to use various variations known in the art, which are not mentioned in more detail herein.

If desired, starting materials may also be formed in situ so as not to be isolated in the reaction mixture but soon further to give compounds of formula (I).

In the compound of formula II, the radical L is preferably Cl or Br, but it is also an I, OH or a reactively modified OH group, for example alkylsulfonyloxy (preferably methylsulfonyl) Oxy) or arylsulfonyloxy (preferably phenylsulfonyloxy, p-tolylsulfonyloxy or 1- or 2-naphthalenesulfonyloxy) having 6 to 10 carbon atoms.

The methods used to react the compounds of formula (II) with the compounds of formula (III) are those known in the literature on the acylation of amines. The components may also be melted together, optionally in a sealed tube or autoclave, without the presence of a solvent.

The compounds of formula III can also be used in the form of their salts, as illustrated by Davidson et al., Synthetic Commun, 20, 727-732 (1990).

However, the compound can also be reacted in the presence of an inert solvent.

Examples of suitable inert solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tertiary butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether (methyl glycol or ethyl glycol) or ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate; And optionally also a mixture of said solvents or a mixture of these with water.

Acid binders, for example alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates or other alkali metal or alkaline earth metal salts of weak acids, preferably potassium, sodium or calcium salts of weak acids, or triethyl It may be desirable to add an organic base or excess amine component such as amine, dimethylamine, pyridine or quinoline. The reaction time is several minutes to 14 days, which depends on the conditions used, and the reaction temperature is -20 to 100 ° C, generally -10 to 40 ° C.

Bases of formula (I) can be converted to the corresponding acid addition salts using an acid, for example by reacting an equivalent amount of the base with an acid in an inert solvent such as ethanol and then evaporating the solution. Particularly suitable acids for this reaction are those with biological compatibility. Thus, inorganic acids such as sulfuric acid, nitric acid, hydrohalic acid such as hydrochloric or hydrobromic acid, phosphoric acid such as orthophosphoric acid or sulfamic acid; And organic acids, in particular aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic acids, sulfonic acids or sulfuric acids such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pi Melic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isoninicotinic acid, methanesulfonic acid or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfuric acid Phonic acid, p-toluenesulfonic acid, naphthalene monosulfonic acid and naphthalenedisulfonic acid or lauryl sulfate can be used. Salts with acids that are not biologically compatible, such as picrates, can be used to isolate and / or purify compounds of formula (I).

In contrast, the compounds of formula (I) can be converted to the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or corresponding ammonium salts, using bases (eg sodium hydroxide or potassium or sodium carbonate or potassium).

The invention also provides the use of a compound of formula (I) as an intermediate in the synthesis of a medicament.

The present invention also provides the use of the compound of formula (I) of claim 1 in a reduction reaction, wherein the reaction of formula (I) is carried out using complex metal hydrides.

Reduction of ketoamides according to the invention is described, for example, in Deslongchamps et al., Using lithium aluminum hydride. J. Chem. 53, 3613-3619 (1975).

Examples of other reducing agents that can be used are NaBH ₄ or NaAl (OCH ₂ CH ₂ OCH ₃ ) ₂ H ₂ , and diborane, and optionally a catalyst such as BF ₃ , AlCl ₃ or LiBr can be added. Examples of suitable solvents are the inert solvents mentioned above.

All temperatures are given herein in degrees Celsius. “Typical aftertreatment” has the following meaning in the examples: water is added, if necessary the pH is adjusted to 2-10, and if necessary the mixture is extracted with ethyl acetate or dichloromethane depending on the composition of the final product. The phases are separated, the organic phase is dried over sodium sulfate and evaporated and the residue is purified by chromatography on silica gel and / or crystallization. Rf value is on silica gel.

Example 1

4- (4-oxocyclohexyl) benzoyl chloride (0.75 mole (130.7 g) of 4-phenylcyclohexanone and 1 mole of oxalyl chloride and 2 moles of AlCl ₃ in dichloromethane are reacted and iced with ice water / HCl) Obtained by decomposition) is added to 3 moles of an aqueous solution of dimethylamine (15%) and the mixture is stirred at 0-5 ° C. for 2 hours. This was worked up by the conventional method to obtain 125.2 g of N, N-dimethyl-4- (4-oxocyclohexyl) benzamide. Melting point: 118 ° C .; Yield: 68% based on 4-phenylcyclohexanone.

Example 2

Equivalent amounts of (4-oxocyclohexyl) benzoyl chloride and dimethylamine hydrochloride are dissolved in dichloromethane. Then, an equivalent amount of triethylamine is added and the mixture is stirred for 3 hours.

N, N-dimethyl-4- (4-oxocyclohexyl) benzamide having a melting point of 118 ° C. is obtained after conventional workup.

Claims (5)

Benzamides of formula I and salts thereof Formula I Where R ¹ and R ² are independently of each other alkyl having 1 to 6 carbon atoms, or R ¹ and R ² together form an alkylene. The method of claim 1, N, N-dimethyl-4- (4-oxocyclohexyl) benzamide and salts thereof. A benzamide of formula (I) according to claim 1, characterized in that a compound of formula (II) is reacted with a compound of formula (III) or one of its salts and / or a base of formula (I) is treated with an acid and converted to one of its salts Method of preparation of salts: Formula II Formula III HNR ¹ R ² Where L is Cl, Br, OH or a reactive esterified OH group, R ¹ and R ² are as defined in claim 1. Use of a compound of formula (I) as claimed in claim 1 as an intermediate in the synthesis of a medicament. Use of a compound of formula (I) as claimed in claim 1 in which the reaction of compound of formula (I) is carried out using a complex metal hydride.