CH629482A5 - Process for the preparation of 1-(4-isopropylmercaptophenyl)-2-N-octylamino-propanol - Google Patents

Abstract

The invention relates to a novel process for the preparation of 1-(4-isopropylmercaptophenyl)-2-N-octylamino-propanol by reduction with sodium borohydride and subsequent acidic hydrolysis of 1-(4-isopropylmercaptophenyl)-1-(trimethylsilyloxy)-2-N-octylamino-pro pene.

Description

The present invention relates to a new process for the preparation of l- (4-isopropylmercapto-phenyl) -2-n. octylamino-propanol (I):

25

known in therapy as Suloctidil. This compound is prepared, according to the technique known up to now, starting from 4-isopro-pilmercapto-propiophenone, usually through the corresponding bromoketone which is reacted with n. Octyl-30 na; there follows the reduction of l- (4-isopropylmercapto-phenyl) -2 - n.octylamino-propanone-1 thus obtained to the final product (I).

The preparation of the intermediate bromoketone has drawbacks due on the one hand to the simultaneous formation, albeit in small quantities, of other bromoderivatives, on the other hand to the aggressiveness of the bromoketone itself, which like all the compounds of this category is a powerful allergen. The subsequent reaction with n.octylamine and the final reduction are characteristics of mediocre yields; both in the case of insulation of the intermediate octylaminoketone, and, and even worse, in the case that the two passages are carried out in direct succession.

The other methods described for the preparation of the compound (I) are devoid of practical interest, either for the negligible yields 45 of the relative steps, or for the prohibitive cost of the reagents involved.

It has now been found that compound (I) can be accessed with excellent yields and without the use of toxic or expensive intermediates if the l- (4-isopropyl-mercapto-phenyl) -l- (tri- 50 methylsilyloxy) -2-n.octylamino-propene (II) and the reaction mixture thus obtained is subjected to acid hydrolysis directly, according to the scheme:

55

Ar

(CH,) Si-0-C = C-CH NH

t

C8H17

1) NaBH,

(THE)

2) HCl

(II)

05 where Ar represents the 4-isopropylmercapto-phenyl residue. The intermediate (II) is in turn easily accessible starting from 4-isopropylmercapto-propiophenone (III), through the following sequence of reactions:

3

629482

^ (CH) Yes Cl f1 *

a) CO-CH2-CH3 ^ (CH3) 3 Si-0-C = CH-CH3;

Et N

(III) 3 (iv)

Ar

, v / TVv N-chlorosuccinimide \ "1

(IV) y (CH3) 3Si-0-C = C-CH3;

Cl

(V)

c) (V) n'C8HlY-NH2 ^

where Ar has the meaning already specified.

Both the three reactions a), b) and c) schematized above, and the final transformation of (II) into the desired product run with high yields and without particular drawbacks.

It has also been found that the final compound (I) can be obtained in a particularly simple and advantageous way for the production on an industrial scale directly from the che-tone (III), without isolating any of the intermediates (IV), (V) and (II ) gradually formed. The compound (I) thus obtained has a considerable degree of purity.

The process of the invention will be illustrated by the following example, relating precisely to the preferred embodiment, that is, without isolation of the intermediates.

Example

To a solution of 120 g (1.1 moles) of trimethyl-silyl chloride and 95 g (1.1 moles) of triethylamine in 750 ml of dimethylformamide, 208 g (1 mol) of 4-isopropylmer-capto-propiophenone are added . The mixture is heated under reflux for 36 hours, about 500 ml of dimethylformamide are distilled under vacuum and the residue is taken up with 2 liters of hexane, washed with 2 portions of 1200 ml of saturated aqueous solution of NaHCOs, then cold and quickly with 1 liter of 1,5-mol hydrochloric acid, then again with 1 liter of saturated solution of NaHC03.

20 The organic phase is evaporated to dryness and taken up again with 800 ml of chloroform.

To the chloroform solution 90 ml of p-ridine and 130 g (1 mole) of N-chlorosuccinimide are added. The mixture is left under stirring for 24 hours at room temperature; then to the 25 solution of l- (4-isopropylmercapto-feniI) - l- (trimethylsilyloxy - methyl) -2-chloropropene (V) thus obtained, 130 g (1 mole) of n.octylamine and 86 g (1 mole) of triethylamine, dissolved in 400 ml of chloroform. The mixture is stirred for 3 hours at 40 ° C, the salts are filtered and the solvent is evaporated under reduced pressure 30.

The residue, consisting of a thick reddish oil, is dissolved in 700 ml of methanol. Under stirring, a solution of 30 g of NaBH4 in 200 cc of a 5N aqueous solution of NaOH is added, keeping the temperature 35 at 20-30 ° C.

After the addition, stirring is continued for 30 ', then 10% hydrochloric acid is added up to pH 1-2. The mixture is left under stirring for two hours, the hydrochloride of 1- (4-isopropic Imercapto-phenyl) -2-n.octylamino-pro-40 panol formed is filtered to the pump and washed on the filter with isopropyl ether. After drying 224 g of said hydrochloride are obtained, from which, by treatment with sodium carbonate solution, 198 g of compound (I) are formed, at a melting point of 64-65 ° C, substantially unitary in thin layer chromatography.

v

Claims (3)

629482 1) NaBH, 1) NaBH 2) HCl (II) C8H17 Ar CH-CH-CH. OH NH C8H17 (THE) where Ar has the meaning specified above. 2. Process for the preparation of the product (I), characterized in that the sequence of reactions represented here is followed: 20 CH-CH-NH ~ n.CQH ti. or 17 OH CH • 3 Ar co-c2h5 (CH,), Yes CI. 3 '3 Ar ^ (CH3) 3 Si-0-C = CH-CH3 Et.N N-chlorosuccinimide Ar (CK) Si-0-C = C-CH J J | Cl Ar « (CH3) 3 Si-0-C '€ -CH the NH n.CgH17-NK2 2) HCl Ar i CH-CH-CH i t 3 OH NH the ° 8H17 (THE) I 15 (THE) where Ar represents the 4-isopropylmercapto-phenyl residue. 2 CLAIMS 1. Process for the preparation of l- (4-isopropiI-mer-capto-feniI) -2-no.Iamino-propanol (I), characterized in that it undergoes reduction with sodium borhydride, and subsequent acid hydrolysis , I'l- (4-isopropiI-mercapto-phenyl) -l - (trimethylsilyloxy) -2-n.octylamino-propene (II), according to the scheme: Ar THE (CH ^) Si-0-C = C-CH (II) THE m C8H17 3. Process according to claim 2, characterized in that Pl- (4-isopropylmercapto-phenyl) -2-n. Octylamino-propanol is obtained directly from 4-isopropylmer-capto-propiophenone, through the indicated sequence, without isolation of the intermediate compounds.