JPS603064B2 - Production method of indazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an indazole derivative represented by the general formula (wherein X represents a hydrogen atom, a halogen atom, or a lower alkyl group, and R represents a trimethylene group).

According to the present invention, the compound of formula 1 is produced by methylating a compound represented by the general formula (wherein x and R have the above-mentioned meanings, and R' represents a hydrogen atom or a methyl group). Ru.

The compound of formula 0 used in the present invention is a new compound and is produced, for example, by the following reaction.

In the formula, ×, R and R have the above-mentioned meanings, X' is a halogen atom, R'' is a lower alkyl group or a hydrogen atom, and n is Z. Examples of the compound of formula (B) include 1-( 3'
1-methylaminopropyl)-3-phenyl-5-methylindazole, 1-(3'-aminopropyl)-3-phenylindazole 1-(3'-aminopropyl)-3
-phenyl-5-chloroindazole, 1-(3'-methylaminopropyl)-3-phenyl-5-chloroindazole, 1-(3'-aminopropyl)-3-phenyl-5-promoindazole, etc. are used.

In carrying out the present invention, the compound of formula (2) is reacted with a methylating agent, such as formaldehyde and formic acid or formaldehyde and sodium poron hydride.

Although the formaldehyde used in this case can be used in the form of a polymer or a reactive derivative thereof, it is preferable to use formaldehyde in view of its ease of reaction. The reaction is carried out by dissolving the compound of formula 0 in a solvent such as methanol, ethanol, etc. or in a trout solvent, and the reaction is carried out at room temperature or under supplementation for usually 2 minutes to 5 hours, preferably 30 minutes to 3 hours.
done in time. Preferably, the methylating agent is used in an equimolar amount or in molar excess relative to the compound of formula 0. To isolate the target compound 1 from the reaction mixture, an organic solvent such as benzene, ether, chloroform, etc. is added to the reaction mixture, the organic layer is separated, washed with water, dried, and concentrated under reduced pressure to obtain the target compound. can get.

The target compound 1 obtained is generally an oily substance, and can also be converted into a salt with an inorganic or organic acid, such as a hydrochloride or an oxalate, by a conventional method.

The compound of formula 1 obtained by the present invention is a new compound and is useful as a pharmaceutical having central depressant action, antidepressant action, anti-inflammatory action, etc.

. Preparation Example of Raw Material Compound 0 3 - 7.76 ml of phenyl-5-methylindazole was dissolved in 100 ml of dimethylformamide, 2.0 ml of 50% sodium hydride was added, and the solution was stirred at room temperature for 10 minutes.

Next, 87 g of bromopropionate ethyl ester was added to this and the mixture was allowed to stand at room temperature for 3 minutes. The reaction solution was poured into water, extracted with chloroform, washed with water, dried, and concentrated to give 1-ethoxycarbonylethyl-3-phenyl-5-
135 ml of methylindazole is obtained. Obtained 1-
Dissolve 135 ml of ethoxycarponylethyl-3-phenyl-5-methylindazole in 100 ml of ethanol,
, 40% monomethylamine aqueous solution 15 of Z was added, 2q
time! After overflowing to 500 ml, concentrate under reduced pressure. The residue was dissolved in chloroform, washed with water, dried over trinitrate, 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 128-13p. Elemental analysis value: C, 8 days, ○ H N Calculated value (male) 73.69 6.53 14.32 Actual value (grandchild) 73.49 6.45 14.47 Obtained 11N-monomethyl Carbamoyl ethyl-3-phenylene-5
- Dissolve 5.0 m of methyl indazole in 40 m' of anhydrous tetrahydrofuran, add 1.5 m of lithium aluminum hydride under ice cooling, and heat under reflux for 20 minutes.

Then, after the reaction, water-containing ether and aqueous sodium hydroxide solution were added. Separate the organic layer. Furthermore, 10% is added to this organic layer.
Add aqueous hydrochloric acid to separate the supernatant solution, and add aqueous sodium hydroxide solution to make it basic. This was extracted with benzene, the organic layer was washed with water, dried over salted salt, and concentrated under reduced pressure.
1.8 g of 5-methylindazole hydrochloride are obtained. The compound obtained by recrystallizing this from a mixed solvent of ethanol and ether has a melting point of 148 to 14 pi. Elemental analysis value: C, 3 days as 22M3CI ○ H N Calculated value (%) 68.45 7.02 13.30 Actual value) 68.70 7.05 13.35 Example 11-
1.1 m/methylaminopropyl-3-phenyl-5-methylindazole was dissolved in 20 methanol,
To this was added 0.63 g of formalin aqueous solution (containing 37% formaldehyde), and the mixture was heated at room temperature for 20 minutes.

. Next, 0.30 g of sodium boron hydride was added under ice cooling, and the mixture was incubated at room temperature for 10 minutes. The resulting reaction solution was concentrated under reduced pressure, benzene was added to the residue, washed with water, dried over shibana, and concentrated under reduced pressure to obtain 1-(3'dimethylaminopropyl)-13-phenyl-5-methylindazole. 0
．． 9 yen is obtained as a pond-like substance. When this is treated with acetic acid in a conventional manner, oxalate is obtained. The compound obtained by recrystallizing this from ethanol has a melting point of 1 to 185°C. Elemental analysis value: C day N Calculated value (grandchild) 65.78 6.57 10.96 Actual value (later) 65.84 6.19 11.00 Example 21
-(3'-Aminopropyl)-3-Phenylindazole 2.0 times, formalin aqueous solution 1.0 times and sodium boron hydride 0.55 times were used, and the other conditions were the same as in Example 1. 1.6 g of 3-phenylindazole (dimethylaminopropyl) are obtained as an oil.

The compound obtained by converting this into a hydrochloride salt by a conventional method and recrystallizing it from a mixed solvent of ethanol and ether has a melting point of 141.
~ Shows 14 Mori 0. Elemental analysis value: C, 8 days 22N3CI
・Assuming 20, ○ H N calculated value (object) 61.44 7
．． 45 11.94 Actual value (after) 61.09 7-40
11.71 Example 31-(3'-aminopropyl)
-3-Phenyl-5-chloroindazole 3.0 Aqueous formalin solution (containing 37% formaldehyde) 7.5
After adding 1.4 g of diluted acid and 1.4 g of sulfuric acid and heating under reflux for 3 hours,
Add sodium hydroxide aqueous solution to make it chlorinated.

Next, 20% of benzene was added and the organic layer was separated, washed with water, dried with salt water, and concentrated under reduced pressure to give 11(3'-dimethylaminopropyl)13-phenyl-5-chloroindazole 2.9 The oil is obtained as an oil. When this is treated with ether-hydrochloric acid in a conventional manner, the hydrochloride is obtained. The compound obtained by recrystallizing this from an ethanol-ethanol mixed solvent exhibits a melting point of 1 to 16 points. . Elemental analysis value: C day 2, N3CI2 as C day N Calculated value (side) 61.72 6.04 12.00 Actual value (%) 61.51 6.01 11.92 Example 41
-(3'-monomethylaminopropyl)-3-phenyl-5-chloroindazole 2.0 mm, chloric acid 0.95 mm, and formalin aqueous solution (containing 37% formaldehyde) 4
．． Using 0 evening and otherwise processing in the same manner as in Example 3,
1.8 ml of 1-(3'-dimethylaminopropyl)-3-phenyl-5-chloroindazole is obtained as a pond.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X represents a hydrogen atom, a halogen atom, or a lower alkyl group, R represents a trimethylene group, and R' represents a hydrogen atom or a methyl group.) A method for producing an indazole derivative represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein X and R have the above-mentioned meanings), which is characterized by methylating a compound represented by