KR790000938B1 - Process for the preparation of indazole derivatives - Google Patents

Abstract

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Description

Preparation of indazole derivatives

The present invention is a general formula

(In the formula, X represents a hydrogen atom, a halogen atom or a lower alkyl group, R represents a lower alkylene group).

According to the present invention, the compound of I is a general formula

Wherein X and R have the meaning of electricity and R 'represents a hydrogen atom or a methyl group.

It is manufactured by methylating the compound represented by.

The compound of formula II used for this invention is a novel compound, For example, it is manufactured by the following reaction.

Wherein X, R and R 'have the meaning of electricity, X' represents a halogen atom, R "represents a lower alkyl group or a hydrogen atom, and n represents an integer of 1-4.

As the compound of Formula II, for example, 1-methylaminopropyl-3-phenyl-5-methylindazole, 1-aminopropyl-3-phenylindazole, 1-aminopropyl-3-phenyl-5-chloroindazole , 1-methylaminopropyl-3-phenyl-5-chloroindazole, 1-aminopropyl-3-phenyl-5-bromidazole, 1-aminoethyl-3-phenyl-5-indazole, 1-aminoethyl 3-phenyl-5-methylindazole, 1-aminobutyl-3-phenylindazole and the like are used.

In carrying out the present invention, the compound of formula II is reacted with a methylating agent such as formaldehyde and acid, or formaldehyde and sodium boron hydride. The formaldehyde used at this time can be used in the form of a polymer or a reactive derivative thereof, but it is preferable to use formalin in view of easy reaction. The reaction is carried out by dissolving the compound of formula II in a solvent such as methanol, ethanol or the like, or without solvent, and usually 20 minutes to 5 hours, preferably 30 minutes to 3 hours at room temperature to warm. It is preferable to use the molar amount or excess molar amount of a methylating agent with respect to the compound of Formula II.

To isolate the target compound I from the reaction mixture, an organic solvent such as benzene, ether, chloroform or the like is added to the reaction mixture, and the organic layer is preparated, washed with water, dried and concentrated under reduced pressure to obtain the target compound.

Obtained target compound I is generally an oily substance, and can also be salted with inorganic or organic acids, for example, hydrochloride or oxalate, by a conventional method.

The compound of formula I obtained by the present invention is a novel compound and is useful as a medicine having central inhibitory action, antidepressant action, anti-inflammatory action and the like.

[Preparation Example of Raw Material Compound II]

7.7 g of 3-phenyl-5-methylindazole is dissolved in 100 ml of dimethylformamide, 2.0 g of 50% -containing sodium hydride is added and stirred at room temperature for 10 minutes. Subsequently, 8.7 g of ethyl bromopropionate is added to this, and it stirred at room temperature for 30 minutes. The reaction solution was poured into water, extracted with chloroform, washed with water, dried and concentrated to give 13.5 g of 1-ethoxycarbonyl-ethyl-3-phenyl-5-methylindazole. 13.5 g of 1-ethoxycarbonylethyl-3-phenyl-5-methylindazole obtained is dissolved in 100 ml of ethanol, 15 ml of a 40% monomethylamine aqueous solution is added, and heated at 50 ° C for 20 hours, followed by concentration under reduced pressure. The residue was dissolved in chloroform, washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 9.0 g of 1-N-monomethylcarbamoylethyl-3-phenyl-5-methylindazole. The compound obtained by recrystallizing this from ethanol has a melting point of 128 130 ° C.

5.0 g of 1-N-monomethyl carbamoylethyl-3-phenyl-5-methylindazole obtained was dissolved in 40 ml of anhydrous tetrahydrofuran, 1.5 g of lithium aluminum hydride was added thereto under ice cooling, and heated under reflux for 20 minutes. Stir. Subsequently, hydrous ether and aqueous sodium hydroxide solution are added to the reaction solution, and the organic layer is separated. Again, 10% hydrochloric acid is added to the organic layer, the supernatant is separated, and sodium hydroxide aqueous solution is added to make it basic. This was extracted with benzene, the organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure, whereby 1.8 g of 1-monomethylaminopropyl-3-phenyl-5-methylindazole hydrochloride was obtained. The compound obtained by recrystallizing this from an ethanol ether mixed solvent shows melting | fusing point 148-149 degreeC.

Example 1

1.1 g of 1-monomethylaminopropyl-3-phenyl-5-methylindazole is dissolved in 20 ml of methanol, and an aqueous formalin solution (containing 37% formaldehyde) 0.63 (to this is added) and stirred at room temperature for 20 minutes.

Subsequently, 0.30 g of sodium boron hydride is added under ice-cooling, followed by stirring at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, benzene was added to the residue, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 0.9 g of 1-dimethylaminopropyl-3-phenyl-5-methylindazole as an oily substance. When this is treated with hydroxyl by the conventional method, the hydroxide is obtained. The compound obtained by recrystallizing this from ethanol shows melting | fusing point 184-185 degreeC.

Example 2

When 2.0 g of 1-anonopropyl-3-phenylindazole, 1.0 g of formalin aqueous solution and 0.55 g of sodium boron hydride were used, and else the same treatment as in Example 1, 1-dimethylanonopropyl-3-phenyl 1.6 g of indazole is graded as an oil. The compound obtained as a hydrochloride by the conventional method and recrystallized from the ethanol ether mixed solvent shows melting | fusing point 141-143 degreeC.

Example 3

To 3.0 g of 1-anonopropyl-3-phenyl-5-chloroindazole, 7.5 g of formalin aqueous solution (containing 37% formaldehyde) and 1.4 g of acid were added thereto, and the mixture was heated and refluxed for 3 hours. do. Then, 20 ml of benzene is added, the organic layer is separated, washed with water, dried over sodium sulfate, and concentrated under reduced pressure, whereby 2.9 g of 1-dimethylanopropyl-3-phenyl-5-chloroindazole is obtained as an oily substance. When this is treated with ether hydrochloric acid by the conventional method, hydrochloride is obtained. The compound obtained by recrystallizing this from an ethanol ether mixed solvent shows melting | fusing point 158-160 degreeC.

Example 4

2.0 g of 1-monomethylanonopropyl-3-phenyl-5-chloroindazole, 0.95 g of phosphate, and 4.0 g of an aqueous solution of formalin (containing 37% formaldehyde) were used. 1.8 g of 1-dimethyl aminopropyl-3-phenyl-5-chloroindazole is obtained as an oil. This can be made into a hydrochloride by the conventional method.

Claims (1)

Method for preparing an indazole derivative of the general formula (I) below, characterized by methylating a compound of the general formula (II)

In each formula above, X is a hydrogen atom, a halogen atom or a lower alkyl group, R is a lower alkylene group, R 'represents a hydrogen atom or a methyl group.