JPS5944313B2 - Manufacturing method of indazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula R and R2 may be the same or different and represent a hydrogen atom or a lower alkyl group, and R1
and R2 may be combined to form a heterocyclic ring optionally substituted with a phenyl group).

According to the invention, the compounds of formula (I) have the general formula (X.
R. R1 and R2 have the above meanings).

In the compounds of formula 1 and formula, examples of the residue of the heterocyclic ring formed by bonding R and R2t)5 include B5 such as morpholino group and piperazino group, and these residues are substituted with a phenyl group. It's okay.

The compound of the formula used in the present invention is a new compound, and
For example, JP-A-51-59 produced by the following reaction
(See Publication No. 862). In the formula, X, R. R and R2 have the above-mentioned meanings, X'' represents a halogen atom, and R' represents a lower alkyl group. Examples of compounds of the formula include the following.

1-N-monomethylcarbamoylethyl-3-phenylintazole, 1-N-monomethylcarbamoylethyl-3-phenyl-5-chloro- and -5-methylindazole 1-N-phenylpiperazinocarbonylethyl-3 -phenyl-5-methylintazole, I-N,N
-dimethylcarbamoylethyl-3-phenyl-5-methylindazolyl, 1-carbamoylethyl-3-phenyl-5-chlorointazole.

In carrying out the present invention, the reduction reaction of the compound of the formula is carried out by dissolving the compound () in an appropriate solvent such as tetrahydrofuran, ether, etc., and adding thereto an equimolar amount to an excess molar amount of a conventional reducing agent such as lithium aluminum hydride. The reaction is carried out for 10 to 60 minutes at room temperature or higher, preferably at the reflux temperature of the reaction mixture. Isolation and purification of the target substance (1) are carried out by conventional methods.

For example, adding aqueous ether dropwise to the reaction mixture under ice cooling,
Further, an aqueous alkali solution such as a sodium hydroxide solution is added to decompose the unreacted reducing agent, and the organic layer is separated. The organic layer is washed with water, dried and concentrated under reduced pressure to obtain the target substance. The target substance is generally obtained as an oil, which can be converted into an appropriate inorganic or organic acid salt, such as hydrochloride, oxalate, tartrate, malonate, etc., 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., and also as an intermediate for the synthesis thereof.

Example 1 5.0 g of 1-N-monomethylcarbamoylethyl-3-phenyl intazole (melting point 111-112-C) was dissolved in 40 strips of anhydrous tetrahydrofuran, 1.5 g of lithium aluminum hydride was added under ice cooling, and the mixture was stirred. Heat to reflux for 20 minutes.

Next, aqueous ether and an aqueous sodium hydroxide solution are added to the reaction mixture, the organic layer is separated, 10% hydrochloric acid is added to the organic layer, and the supernatant liquid is separated. The supernatant liquid was made basic by adding an aqueous sodium hydroxide solution, and then extracted with benzene. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 1-N-
1.29 g of monomethylaminopropyl-3-phenylintazole are obtained as an oil. This is made into oxalate by a conventional method. When this oxalate salt is recrystallized from methanol, it exhibits a melting point (decomposition) of 197-198°C. Example 2 1-N-monomethylcarbamoylethyl-3-phenyl-5-chlorointazole (melting point 123-1251C)
5.09, lithium aluminum hydride 1.5
f! When treated in the same manner as in Example 1, 2.09 g of 1-N-monomethylaminopropyl-3-phenyl-5-chlorointazole oxalate is obtained.

When this is recrystallized from methanol, it exhibits a melting point (decomposition) of 203-204°C. Example 3 1-N-Monomethylcarbamoylethyl-3-phenyl-5-methylintazole (melting point 128-13'C) 5.09 was treated in the same manner as in Example 1 using lithium aluminum hydride 1.59. 1-N-monomethylaminopropyl-
3-phenyl-5-methylintazole hydrochloride 1.89
is obtained.

When this is recrystallized from a mixed solvent of ethanol and ether, it exhibits a melting point of 148-149°C. Example 4 1-Hydroxycarbonylethyl-3-phenyl-5-
1-N-phenylpiperazinocarbonylethyl-3-phenyl-5- obtained by sequentially reacting chlorocarbonethyl and N-phenylpiperazine with methyl intazole
When 4.09% of methyl intasol (oil) is treated with 1.29% of lithium aluminum hydride in the same manner as in Example 1, 1-N-phenylpiperazinopropyl-131 phenyl-5-methylintasol is obtained. Hydrochloride 6.1
9 is obtained.

When this is recrystallized from an ethanol-ether mixed solvent, it exhibits a melting point of 195-200°C. Example 5 1-N,N-dimethylcarbamoylethyl-3-phenyl-5-methylintazole (melting point 99-1000C)
5.0f! , lithium aluminum hydride 1.
59 and treated in the same manner as in Example 1, l-N,N
1.99 of -dimethylaminopropyl-3-phenyl-5-methylintasol oxalate are obtained.

When this is recrystallized from ethanol, it shows a melting point of 184-185°C. Example 6 When 5.09 g of 1-carbamoylethyl-3-phenyl-5-chlorointasol (melting point 156-1575 C) was treated with 1.59 g of lithium aluminum hydride in the same manner as in Example 1, 1-aminopropyl -3-phenyl-5-chlorointasol hydrochloride 2.09t)S
can get.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (In the formula, X is a hydrogen atom, a halogen atom or a lower alkyl group, R is a lower alkylene group, R_1 and R_2 are the same or different may represent a hydrogen atom or a lower alkyl group, and R_1 and R
There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ ( I) A method for producing an indazole derivative represented by the formula (wherein X, R, R_1 and R_2 have the above-mentioned meanings).