IE49400B1

IE49400B1 - 2-benzyl-3-(-3-chloro or hydroxy propylithio)-indazole,their corresponding sulfoxides and sulfones and process for their preparation

Info

Publication number: IE49400B1
Application number: IE239583A
Authority: IE
Original assignee: Acraf
Priority date: 1979-02-19
Filing date: 1980-02-18
Publication date: 1985-10-02
Also published as: IE49401B1; IE832395L

Description

The present invention relates to intermediates useful in the preparation of 2-benzyl-3-(3-dimethylaminopropylthio2H-indazole (I) as well as its sulfoxide (II) and its su1fone (III): x N II The above compounds are described and claimed in our Rccfent - 3 Pharmacological studies carried out on laboratory animals have shown that the above compounds possess an antiinflamatory activity, which manifests itself both through the topical and the systemic route, as well as a local anaesthetic activity and a disinfectant action which manifest themselves only after topical application.

In the above compounds (I), (II) and (III) may be prepared by a variety of routes including the reaction of 2-benzylindazolin-3-thione (IV) with l-bromo-3-chloro (or hydroxy) propane according to the following scheme.

Where X is Cl or OH. - 4 The novel intermediate compounds of the present invention are those of formula (VI) and the corresponding sulfoxides and sulfones.

In the above reaction scheme the 2-benzyl-indazolin-35 thione (IV) reacts easily with 1-bromo-3-chloropropane in the presence of a base both in polar and non-polar solvents, to give the 2-benzyl-3-(3-chloropropylthio)indazole (VI ) in good yields, a For X = OH, the 2-benzyl-3-(3-hydroxypropylthio)10 indazole may also be prepared by the action of the 3ch1oropropanol on the sodium salt of (IV).

Compound (VI) (X = chlorine) reacts with solutions of dimethylamine in both polar and non-polar solvents to give (I) as the hydrochloride.

The use of gaseous dimethylamine is obviously possible but in general, unless special installations are used, it is less advantageous as will become clear to one skilled in the art.

When then, in (VI), X = OH, the reaction with dimethylamine will require the use of a catalyst, such as dicyclohexylcarbodi i mi de. - 5 Also in accordance with the present invention compound (VI) may be oxidized with peracids to provide the corresponding sulfoxides and sulfones (VII and VIII) according to the peracid used and the reaction conditions selected.

By action ofihe dimethylamine in conditions similar to that described for the preparation of (I), from (VII) and (VIII) there can then be obtained (II) and (III): The present invention is illustrated by the following Examples. - 6 EXAMPLE 1 2-benzyl-3-(3-chloropropylthio)-indazole 2-benzyl-indazolin-3-thione (44.3 g, 0.185 mols) is dissolved in a solution of 12.9 g (0.230 mols) of KOH in 500 ml of water. When the solution is completed there is added 31.9g (0.203 mols) of l-bromo-3-chloropropane. The mixture is heated with stirring on a steam bath for 3 hours and is then cooled.

The oil which forms is extracted with ether and the 10 residue which is obtained by removing the solvent (59 g; yield: 100%) results unitary under TLC and its NMR is in accordance with the expected structure.

EXAMPLE 2 2-benzyl-3-(3-hydroxypropylthio)-indazole To a solution of 0.92 g (0.04 mols) of sodium in 100 ml of absolute ethanol there is added 9.6 g (0.04 mols) of 2benzyl-indazolin-3-thione. The ethanol is removed on a steam bath under reduced pressure and the dry sodium salt thus obtained is suspended in 50 ml of 3-chloropropanol.

The mixture is heated for 3 hours with stirring in a bath kept at a temperature of 180°. At the end of the heating cycle the mixture is poured in water and extracted with - 7 ether. The ether extract is dried and the solvent is removed under high vacuum while it is heated in an oil bath at 130° to eliminate also the excess portion of 3-chloropropanol which has been extracted with the ether.

The oily residue is purified by chromatography on a silica gel column, using as the eluent ethyl acetate.

The resulting oil (7.3 g - yield: 61%), which tends to decompose if distillation thereof is attempted, shows by elemental analysis and under NMR spectrum to consist of practically pure 2-benzyl-3-(3-hydroxypropylthio)-indazole.

Claims

1. 2-Benzyl-3-(3-chloropropylthio)-indazole.

2. A method for the preparation of the compound claimed in claim 1, which comprises reacting 2-benzyl-indazolin-35 thione in the presence of a base with l-bromo-3-chloropropane.

3. 2-Benzy1-3-(3-hydroxypropylthio)-indazole.

4. A method for the preparation of the compound claimed in claim 3, which comprises reacting the sodium salt of 2benzyl-indazolin-3-thione with 3-chloropropanol. io

5. The sulfoxides and sulfones of the compounds claimed in claim 1 and 3. ejj tlai-m 1,3 et S'

6. A compoundsubstantially as hereinbefore described with reference to the Examples. (x&Jxl/K'ng a. J 4/3 trt-5

7. A methodjjubstantially as hereinbefore described with 15 reference to the Examples.