PROCESS FOR THE PREPARATION OF SUBSTITUTED PHENYLHYDRAZONES

METHODE DE PREPARATION DE DERIVES DE SUBSTITUTION DE PHENYLHYDRAZONES

English Abstract

The invention relates to an improved process for
the preparation of substituted phenylhydrazones, starting
from aniline derivatives and 1,3-dicarbonyl compounds,
and to the use of the compounds thus prepared for the
preparation of indoles.

Claims

- 8 -
Patent claims
1. Process for the preparation of substituted
phenylhydrazones from a diazonium salt and a 1,3-dicar-
bonyl compound in which the following steps are carried
out in succession:
a) reaction of an aniline derivative with hydrochloric
acid,
b) addition of an aqueous solution of sodium nitrite,
c) reaction with the 1,3-dicarbonyl compound in an
inert solvent,
characterized in that in step c) a water-immiscible
solvent is used, preferably an aromatic hydrocarbon.
2. Process for the preparation of phenyl hydrazones
of the formula I
<IMG> I
in which
Ar is a phenyl group which is unsubstituted or is
substituted by one or more alkyl or alkoxy groups,
R1 is a C1-C8-alkyl group, and
n is 2,3,4 or 5,
characterized in that an aniline derivative of the
formula II
<IMG>
in which Ar is as defined
is reacted with a 2-alkoxycarbonylcycloalkanone of the
formula III,

- 9 -
<IMG> III
in which R1 and n are as defined, in accordance with
Claim 1, and d) is then treated with a base, preferably
with an alkali metal hydroxide or alkaline earth metal
hydroxide.
3. Process according to one of Claims 1 and 2,
characterized in that in step c) a pH of between 5.0 and
7.5 is established.
4. Process according to one of the preceding claims,
characterized in that steps a) to c) are carried out in
one apparatus without working up in the interim and at
temperatures of between -20° and +25°C.
5. Process according to one of Claims 2, 3 and 4,
characterized in that in step d) the base is metered in
slowly such that a pH of between 9.0 and 4.0, preferably
8.0 and 5.0, is maintained.
6. Process according to one of the preceding claims,
characterized in that the reaction is carried out with
stirring and under an inert gas atmosphere.
7. Use of the substituted phenylhydrazones prepared
according to one of the preceding claims for the prepara-
tion of indoles, characterized in that they are subjected
in a manner known per se to the conditions of the Fischer
indole synthesis.

Description

9 ~
-- 1
De~cription
The invention relates to a process for the
preparation of substituted phenylhydrazones from a
diazonium salt and a 1,3-dicarbonyl compound. Substituted
phenylhydrazones are valuable intermediates in the
preparation of substituted indoles.
These compounds have previously been prepared in
a two-stage process starting from the correspo~ing
aniline derivatives:
The aniline derivative was first converted into
an anilinium hydrochloride which, after isolation, was
treated with an aqueous solution of sodium nitrite.
Subsequently the diazonium salt obtained in this way was
reacted in a water-soluble medium with the 1,3-dicarbonyl
compound.
However, if the anilinium hydrochloride is
employed for the preparation of the phenylhydrazones
without isolating it beforehand in the manner indicated,
the product is obtained in the form of a dark brown
greasy mass which does not crystallize even after addi-
tion of nonpolar solvents and cannot be worked up or
separated off.
The object of the present invention was to
discover a process in which the anilinium hydrochloride
need not be prepared and isolated in a prior reaction but
is prepared directly in situ and processed further.
Surprisingly it has now been found that the prior
isolation can be avoided, while nevertheless obtaining
crystalline products, if the reaction with the 1,3-
dicarbonyl compound is carried out not, as previously, ina one-phase protic solvent but in a two-phase system with
a water-insoluble solvent.
The invention thus relates to a process for the
preparation of substituted phenylhydrazones from a
diazonium salt and a 1,3-dicarbonyl compound in which the
following steps are carried out in succession:
a~ reaction of an aniline derivative with hydrochloric

21~13~99
- 2 -
acid,
b) addition of an aqueous solution of sodium nitrite,
c) reaction with the 1,3-dicarbonyl compound in an
inert solvent,
characterized in that in step c) a water-immiscible
sol~ent is used, preferably an aromatic hydrocarbon,
especially toluene.
a) Preferred embodiments are: process for the prepara-
tion of phenylhydrazones of the formula I
Ar NH--N--I (CH2)n COOH
COOR'
in which
Ar is a phenyl group which is unsubstituted or is
substituted by one or more alkyl or alkoxy
groups, preferably a phenyl group which is mono-
substituted by Cl10-alkoxy
Rl is a Cl-C8-al~yl group, preferably Cl-C4-alkyl,
and
n is 2,3,4 or 5, preferably 2 or 3, especially 3,
characterized in that an aniline derivative of the
formula II
Ar NH2
in which Ar is as defined
i8 reacted with a 2-alkoxycarbonylcycloAl~no~e of
the formula III,

21~3 19~
-- 3
-
~I~,COOR1
111
(CH2)n
in which Rl and n are as defined, in accordance with
steps a) to c), and d) is subsequently treated with
a base, preferably with an alkali metal hydroxide or
an alkaline earth metal hydroxide, especially with
S concentrated sodium hydroxide solution.
b) Process in which in step c) a pH of between 5.0 and
7.5 is established.
c) Process in which steps a) to c) are carried out in
one apparatus without working up in the interim and
at temperatures of between -20 and +25C.
d) Process in which in step d) the base is metered in
slowly such that a pH of between 9.0 and 4.0, pre-
ferably 8.0 and 5.0, is maintained.
e) Process in which the reaction is carried out with
stirring and under an inert gas atmosphere.
The invention also relates to the use of the
substituted phenylhydrazones prepared by one of Claims 1
to 6 for the preparation of indoles, characterized in
that they are subjected in a manner known per se to the
conditions of the Fischer indole synthesis.
The phenylhydrazones of the formula I are impor-
tant intermediates in the preparation of substituted 3-
indolylalkylamines, valuable pharmaceutical active
substances having antihypertensive and antidepre~sant
properties, especially of ~oY;n~ol~ (e.g. DE 28 27 874).
The process according to the invention is simple
to carry out.
The molar ratio of aniline derivative to hydro-
chloric acid can be chosen as desired. It is usual to

21 13 19~
-- 4
work at a molar ratio of aniline derivative to hydro-
chloric acid in the range from 1:1.8 to 1:4. This ratio
is preferably from 1:2.0 to 1:2.8.
In general the hydrochloric acid i8 introduced as
initial charge and the aniline derivative is added. The
hydrochloric acid i~ preferably employed in the form of
a 10 to 37 % aqueous solution.
An aqueous solution of sodium nitrite is added to
the resulting aqueous solution of the anilinium hydro-
chloride. The molar ratio of aniline derivative to sodiumnitrite is generally from 1:0.8 to 1:1.2, preferably from
1:0.9 to 1:1.1 and in particular from 1:1.0 to 1:1.05.
The solution of sodium nitrite is preferably em-
ployed in the form of a 30 to 60 % solution.
~nder the conditions indicated the formation of
the diazonium salt i~ generally complete after from 10 to
120 minutes.
The addition of the inert, water-immiscible
solvent can be carried out before, during or after the
addition of the 1,3-dicarbonyl compound. The 1,3-dicar-
bonyl compound is preferably added, dissolved in the
inert solvent, to the aqueous solution of the diazonium
salt.
The molar ratio of aniline derivative to 1,3-
dicarbonyl compound is preferably chosen such that from
0.8 to 1.2 mol, particularly preferably from 0.9 to
1.1 mol and in particular about 1.03 mol of 1,3-dicar-
bonyl compound are employed per mole of aniline deriva-
tive employed.
The weight ratio of 1,3-dicarbonyl compound of
the inert solvent is generally chosen such that from 2 to
5 parts, preferably from 2.5 to 3.5 parts and in
particular from 3 to 3.5 parts of solvent are employed
per part of l,3-dicarbonyl compound.
The process according to the invention can be
carried out, for example, at temperatures in the range
from -25 to +25C. Preferred temperatures are in the
range from -10 to +10C, particularly preferably in the
range from -5 to +5C. The process according to the

2143~99
invention is usually carried out at atmospheric pressure.
However, it i8 also possible for it to be carried out at
reduced or elevated pressure. The application of elevated
pressure is particularly appropriate if it is desired to
work at a reaction temperature at which the individual
constituents of the reaction mixture boil at atmospheric
pressure .
Solvents which are ~uitable are hydrocarbons,
preferably aromatic hydrocarbons, such as benzene,
toluene or xylene, especially toluene.
In the formulae I and II Ar is preferably a
phenyl group which is substituted by from one to four,
preferably one or two, C1-C10-alkyl or alkoxy groups.
In the compounds specified, at least one position
ortho to the nitrogen atom is unsubstituted, but prefer-
ably these compounds contain no substituent~ in the
position ortho to the nitrogen atom.
In the preparation of the compounds of the
formula I, a base is added to the mixture in step d).
Bases which are suitable for the process
according to the invention are generally inorganic bases,
for example alkali metal hydroxides and alkaline earth
metal hydroxides. Particular preference i8 given to using
sodium hydroxide or potassium hydroxide.
The ratio of the dicarbonyl compound employed to
the base is preferably chosen such that from 0.9 to 1.7
equi~alents, particularly preferably from 1.1 to 1.5
equivalents, of base are employed per equivalent of 1,3-
dicarbonyl compound.
The base is preferably added in the form of an 8
to 32 % aqueous solution. The addition is preferably made
while monitoring the pH. At the end of the reaction a
weakly acid pH of between 4.0 and 6.0, in particular
between 5.0 and 5.5, is established.
The working-up of the reaction mixture is not
critical. The product crystallizes out after 18 h, and
preferably after from 30 to 48 h the crystals are iso-
lated by filtration or centrifugation, washed with water
and toluene and dried.

21~3~9~
- 6 -
The phenylhydrazones of the formula I are con-
verted in a manner known per se, for example in accor-
dance with W.J. Houlihan, ed., Chemistry of Heterocyclic
Compounds - Indoles Pt 1, pp. 232-316 (1972) by reaction
with Lewis acids, especially with zinc chloride, into the
indoles of the formula III
(R)m ~ (CH2) ,-COOH
in which R1 and n are as defined
R' is alkyl or alkoxy, and
m is O, 1, 2, 3 or 4.
In accordance with the process according to the invention
it is surprisingly possible, starting from aniline
derivatives and 1,3-dicarbonyl compounds, to prepare
phenylhydrazones in high yields and great purity in a
one-part process. Consequently the process according to
the invention is substantially more economical and
achieves higher space-time yields in comparison with the
process of the prior art.
Example 1
74.0 kg of p-anisidine are added, with stirring
and cooling, to a mixture of 138.2 kg of concentrated
hydrochloric acid and 395 1 of water, and the mixture is
stirred at 0C under an inert gas atmosphere for two
hours.
Sub~equently a solution of 42 kg of sodium
nitrite in 60 1 of water is added over the course of
3 hours at temperatures of between O and +2C, and the
mixture is stirred for a further 30 minutes.
Over the course of one hour a mixture of 102 kg
of ethyl cycloh~y~ne-2-carboxylate and 347 kg of toluene
is added at 0C and the mixture is stirred for a further

2 1 Ll 3 1 9 9
- 7 -
hour.
A mixture of 101 kg of 32 % sodium hydroxide
solution and 248 1 of water is added to the resulting
reaction mixture at temperatures of below 5C over the
course of about 4 hours in such a way that a pH of 8 is
not exceeded.
After crystallization, 136 kg of 6-carboethoxy-6-
(4-methoxyphenylhydrazono)hexanecarboxylic acid are
obtained from the reaction mixture (^ 70 % of theory
based on p-anisidine, m.p.: 97C).
Comparative examPle
p-Anisidine is reacted as described in Example 1,
except that the ethyl cyclohexane-2-carboxylate is added
to isopropanol instead of toluene.
A dark brown greasy mass is obtained which - even
after addition of toluene - does not crystallize.