CS200214B2 - Method of preparing indazole derivatives - Google Patents

Description

The invention relates to a process for the preparation of indazole derivatives of the general formula (I) in which:

R 1 is hydrogen or C 1 -C 4 alkyl,

R 'is hydrogen or an acetyl or benzoyl group,

R _{2 is} benzyl or hydrogen when R 'is acetyl or benzoyl.

The novel compounds of formula I have been found to be valuable intermediates for the preparation of beneficial, pharmacologically active substances. Initially, the corresponding 4-hydroxy compounds can be prepared from compounds of formula I wherein R 8 is benzyl, which are then reacted, optionally directly, with reactive N-alkyl alkylamines or via suitable intermediates, for example 3-indazolyl- (4) oxy -propanol- (2) -amines useful as inhibitors of adrenoergic beta-receptors for the treatment or prophylaxis of cardiac and circulatory diseases; for example, treatment of 1-acetyl-4- (2,3-epoxypropoxy) indazole with isopropylamine affords 1- [indazolyl- (4) -oxy-3-isopropylaminopropanol- (2).

Antiallergic active substances and substances acting on the blood circulation can also be prepared by reaction with other components.

A process for the preparation of compounds of formula I is characterized in that the compound of formula II

in which

Rj is as defined above,

Rg is benzyl, r is acetyl or benzoyl, nitrosated, cyclized and then optionally cleaved a benzyl or acetyl or benzoyl group, whereby the compounds of the formula I thus obtained may optionally be converted into other compounds of the formula I.

According to this method, the 3-acylamino-2-methylphenylbenzyl ether of formula II is nitrosated (e.g. with isoamylnitrile) in an aprotic solvent (e.g. toluene) in the presence of an anhydride and an alkali metal salt and acid corresponding to the acyl residue and cyclized by heating. Thereafter, the benzyl group of the compound obtained can be readily hydrogenolytically cleaved.

Sufficient conversion of compounds of formula I to other compounds of formula I may be carried out according to known methods.

It is also possible to selectively remove it under mild conditions by aminolysis or hydrolysis, i.e. without altering other functional groups, from the compounds of formula I wherein R 'is an acyl group.

The preparation of the compounds of the invention will be described in more detail in the following examples.

Example 1

1-Acetyl-4-benzoyloxyindazole

A mixture of 64 g of (3-acetamido-2-methylphenyl) benzyl ether, 25 g of sodium acetate, 69 ml of acetic anhydride, 50 ml of isoamylnitrile and 2 l of toluene is stirred at 80-90 for 15-20 hours.

After cooling to 10 ° C, the salt is filtered off with suction and the filtrate is concentrated to dryness in vacuo. Trituration of the residue with 300 ml of methanol yielded 47.5 g of almost colorless crystals, m.p. 97 ° C.

The (3-acetamido-2-methylphenyl) benzyl ether used as the starting material is obtained in the following two steps:

(3-Amino-2-methylphenyl) benzyl ether

Reduction of (2-methyl-3-nitrophenyl) benzyl ether with hydrazine hydrate and Raney nickel in methanol yields a green oil as a crude product.

(3-Acetamide -2-methylphenyl) benzyl ether

Acetylation of the product described above with acetic anhydride in toluene: colorless crystals, m.p.

142-143 ° C (from toluene).

Example 2

1-Methyl-4-benzyloxy-6-methylindazole

2002.4

A mixture of 149 g of (3-acetamido-2,5-dimethyl-phenyl) benzyl ether, 50 g of sodium acetate, 138 ml of acetic anhydride, 50 ml of isoamylnitrile and 3 l of toluene is stirred at 80-90 ° C for 15-20 hours. After cooling, it is filtered off with suction, the filtrate is concentrated to dryness in vacuo, the residue is dissolved in 300 ml of methanol and the product is crystallized in a cold state. Yield: 103 g of yellowish crystals, mp 91-93 ° C;

The (3-Acetamido-2,5-dlmethyl-phenyl) benzyl ether used in Example 2 as a starting material was prepared by the following reactions from 2,5-dimethyl-3-nitrophenols:

(2,5-Dimethyl-3-nitrophenyl) benzyl ether

A mixture of 433 g of 2,5-dimethyl-3-nitrophenol, 360 g of potassium carbonate, 326 ml of benzyl chloride and 2 liters of dimethylformamide was stirred overnight at 50 ° C. It is suctioned off, the filtrate is concentrated to dryness in vacuo, the residue is poured into 4.1 g of ice-water and after suctioning and air-drying 668 g of yellowish crystals are obtained, m.p. 66-68 ° C.

(3-Amino-2,5-dimethylphenyl) benzyl ther

The nitro compound described above was reduced with hydrazine hydrate using Raney nickel in methanol. A brown oil is obtained in good yield as a crude product.

(3-Aoetamido-2,5-dimethylphenyl) benzyl ether

Acetylation of the product described above with acetic anhydride in toluene: colorless crystals, m.p.

M.p. 169-171 ° C (from toluene).

An analogous procedure yields:

a) from (3-acetamido-2,6-dimethylphenyl) -benzyl ether (mp 161-162 ° C) [prepared via (2,6-dimethyl-3-nitrophenyl) benzyl ether and (3-amino-2,6-dimethylphenyl) ) benzyletherj

1-acetyl-4-benzyloxy-5-methylindazole, mp 108-109 ° C;

b) from (3-azetamido-2,4-dimethylphenyl) benzyl ether (mp 160-162 ° C) [prepared via (2,4-dimethyl-3-nitrophenyl) benzyl ether, mp 65-67 ° C, and (3- amino-2,4-dimethylphenyl) benzyl ether

1-acetyl-4-benzyloxy-7-methylindazole, mp 90-92 ° C;

c) from (2-methyl-3-acetamido-5-ethylphenyl) benzyl ether (mp 139-140 ° C), [prepared via (2-methyl-3-nitro-5-ethylphenyl) benzyl ether and (2-methyl-3) (amino-5-ethylphenyl) benzyl ether

1-Acetyl-4-benzyloxy-6-ethylindazole, mp, 109.5-1.5 ° C.

Example 3

4-Benzyloxy-6-methylindazole

0.5 g of n-acetyl-4-benzyolxy-6-methylindazole was allowed to stand for 1 hour in 10 ml of isopropylamine at room temperature, concentrated to dryness in vacuo and the residue was recrystallized from methanol-water using charcoal. Yield: 0.2 g of colorless crystals, mp 105-107 ° C.

In an analogous manner there are obtained:

a) 4-benzyloxy-5-methylindazole, m.p. 94-95 ° C;

b) 4-benzyloxy-7-methylindazole, m.p. 175-177 ° C.

Example 4

1-Acetyl-4-hydroxyindazole

Hydrogenolysis of 1-acetyl-4-benzyloxyindazole in the presence of palladium on carbon (10%) in methanol at atmospheric pressure gives beige crystals, m.p. 140-142 ° C (from water)

Example 5

1-Acetyl-4-hydroxy-6-methylindazole

Analogously to Example 4, the product crystallizing from methanol in pale yellowish crystals, m.p. 191-192 ° C, was obtained by hydrogenation of 1-acetyl-4-benzyloxy-6-methylindazole.

By analogy, it is obtained:

(a) 1-acetyl-4-hydroxy-5-methylindazole, m.p. 185-186 ° C;

b) 1-acetyl-4-hydroxy-7-methylindazole, m.p. 135-136 ° C;

mp 161-163 ° C, 1-acetyl-4-hydroxy-6-ethylindazole.

Claims (1)

A process for the preparation of indazole derivatives of the general formula I, R. o '(I) in which is R ( _{1) is} hydrogen or (C1-C4) -alkyl, R is hydrogen or acetyl or benzoyl, Rg is benzyl or hydrogen when R 'is an acetyl or benzoyl group, characterized in that the compound of formula II, OR '(II) I £. CH, ^X-NH-R i n _t wherein R is as defined above, R 8 is a benzyl group, and is an acetyl or benzoyl group, nitrosated, cyclized and then optionally cleaved a benzyl or acetyl group, the compounds of the formula I thus obtained optionally being subsequently converted into other compounds of the formula I.