PROCESS FOR THE PREPARATION OF 1-(4-ISOPROPYLMERCAPTO- PHENYL)-2-N. OCTYLAMINOPROPANOL

PROCEDE D'OBTENTION DE 1-(4-ISOPROPYLMERCAPTO-PHENYL)- 2-N. OCTYLAMINOPROPANOL

English Abstract

- 1 -
TITLE OF THE INVENTION
"A PROCESS FOR THE PREPARATION OF 1-(4-ISOPROPYLMERCAPTO-
PHENYL)-2-n.OCTYLAMINOPROPANOL"
ABSTRACT OF THE DISCLOSURE
A process for the preparation of 1-(4-isopropyl-
mercapto-phenyl)-2-n.octylaminopropanol comprising the reduction
of 1-(4-isopropylmercapto-phenyl)-1-(trimethyl-silyloxi)-2-
n.octylamino-propene (II) and the acid hydrolysis of the re-
duction mixture.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. Process for preparing 1-(4-isopropylmercapto-phenyl)-
2-n.octylaminopropanol (I), characterized by the fact that
1-(4-isopropylmercapto-phenyl)-1-(trimethyl-silyloxy)-2-
n.octylamino-propene (II) is reduced with sodium boro-
hydride and successively hydrolyzed in acid medium,
according to the scheme:
<IMG>
(II) (I)
where Ar represents the 4-isopropylmercapto-phenyl group.
2. Process as claimed in claim 1, characterized by the
fact that the compound (II) is obtained according to the
following reactions:
<IMG> (II)
where Ar has the above mentioned meaning.
3. Process as claimed in claim 1 and 2, characterized by

the fact that 1-(4-isopropylmercapto-phenyl)-2-n.octyl-
aminopropanol is directly obtained from 4-isopropyl-
mercapto-propiophenone, through the above indicated
reactions, without isolating the intermediate compounds.

Description

2~ 10
The invention relates to a new process for preparing
1-(4-isopropylmercapto-phenyl)-2-n.oc-tyl~minopropanol of the
formula I
C / 3
C~-CH-NH-n.C8~17
OH CH3
which is a compound endowed with interesting therapeutic pro~
perties (it is ~n~wn as "Suloctidil"). In the pr~ art, the
compound (I) i9 prepared from 4-isopropylmercapto-propiopheno
ne, usually through the corresponding bromoketone, which i9
reacted with nOoctylamine, the 80 obtained 1~(4-i~opropyl-
mercapto-phenyl)-2-n.octylamino-propanone-1 being then reducec
to the end product (I).
~ ho preparation of the intermediate bromoketone presents
some disadvantages due, on one side~ to the simultaneous for
mation (even though to a small extent) of other bromoderivati~
~0.8, on the other to the fact that bromoketone i~ an aggressi
ve compound and~ as all the compounds o~ this kînd~ it is a
strong allergenic agent~ ~he following reaction with n.octyla
mine and the final reductio~ ~re characterized by poor yields
,

i41(~
both if the intermediate octyl~minoketone is isolated and,
and even worse, if the two stages are per*ormed in direct suc
cession.
The other methods described for the preparation of the com-
pound (I) lack of practical intere~t, eitherfor the tri~ling
yields of the corresponding reactionsJ or for the excessive
cost of the involved reagents.
I It has now been found that it is possible to obtain the
¦ compound (I) with very good yields and without using toxic or
expensive intermediates if 1-(4-i~opropylmercapto-phenyl)-1-
(trimeth~l-silyloxy)-2-n.octylamino-propene (II) is reduced
and the so obtained reaction mixture iæ direetly hydrolysed
in acid medium, according to the scheme:
, .
Ir
(CH3)3Si-O-C=C_CH3 1)Na~H4 (I)
; NH 2)HCl
C8H17
(II)
where Ar repre~onts the 4-i~opropyl~ercapto-phenyl group~
The intermediate (II) i5 ea~ily obtainable ~rom 4-isopro
pylmercapto-propiophenone (III) through the ~cheme of reac-
i tion~ b low:

~ 6 ~ ~0
ij ~ 4 )
I
I lr (CH3)3SiCl Ar
¦ ~) C0-CH -CH ~ (CH3)3Si-0-C-CH-CH3 ;
(III~ (IV)
b) (IV) N chloro-~uccinimide ~CH ) 3i-0-C~-CH ;
~ 3 3 3
(V)
c) (V) B 17 2 (II)
where Ar has the above mentioned me~ning~ Both the three
reactions a), b) a~d c) above indicated and the final trans-
form~tion of (II) in the end product oocur with high yields
and without any difficulty.
It ha~ furthermore been found that the final compound (1~
can be obtained in a ver~ ~imple and advantageou~ way for the
production on industrial ~oale directly from the ketons (III)
without i~olating any of the intermediatee (IV~, (V) and (II)
which are ~ucca~ ely formed. ~he compol~nd (I) thus obtained .
ha~ noteworthy dagree of purity~
The prooes~ of this invention will be explained by the fol-
lowing example~ relatsd to the pre~err~d embodiment, i.e.
without i801ating the intermediate~

1~13Ç6~10
~ - 5 -
EXAMPLE
To a solution of 120 gr (1 1 moles) of trimethylsilylchlo-
rlde and 95 gr (1.1 moles) of triethylamine in 750 ml of
N,N-dimethylformamide, 208 gr (1 mole) of 4-isopropylmercapto
propiophenone are added. ~he mixture i8 refluxed for 36 hours
then about 500 ml of N,N-dimethylformamide are distilled
under vacuum and the residue is treated with 2 liters of
hexane; the solution i6 washed with two portions of 1200 ml
of an aqueous N~C03-saturated solution, then (rapidly and in
the cool) with 1 liter of 1.5-molar Hl, then again with 1
; liter o~ NaH~03-saturated 601ution. ~he organic layer is eva-
porated to dryness and the residue is dissolved in 800 ml of
CHC13.
~o the chloroformic solution, 90 ml of pyridine and 130 gr
(1 mole) of N-chlorosuccinimide ~re added. ~he mixture is
stirred at room temperature for 24 hours; th~ the 80 o~tained
solution of 1-(4-isopropylmer¢apto-phenyl)-1-(trimethylsilyl
oxy-methyl)-2-chloropropene (V) is treated with a solution of
130 gr (1 mole~ of n.octylamine and 86 gr (1 mole) of trieth~
; ~20 lamine i~ 400 ml of CHC13. ~he mixture is stirred at 40C for
3 hours; the precipitated salts are filtered off and the sol-
vent is evaporated under vaouum.
~he re~idue (which is a thiek reddish oil) is dissolved in
700 ml of methanol, then treated under stirring with a solu-
~- ~
~ tion of 30 gr of NaEH4 in 2QO ml of 5-normal aqueous NaOH;
,~ i
,., ~., ~ :
, ' : . : '.' ~
~ ' :

1~6~1~
during this reaction the temperature is maintained at
20-30C.
After the addition, stirring is continued for 30
minutes, then 10% HCl is added until pH 1-2. The mixture
is stirred for 2 hours, the so formed 1-(4-isopropyl-
mercapto-phenyl)-2-n.octylaminopropanol hydrochloride is
filtered by suction and washed with diisopropylether.
After drying 224 gr of said hydrochloride are obtained,
by treating with Na2OC3-solution the corresponding base
(I) is formed (198 gr), m.p. 64-65C; the compound is sub-
stantially unitary in thin layer chromatrography.
r~
.