Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
2~
~ , Background of the Inven~ion
i
i 1) Field of the Invention
This invention relates to a novel process for the
preparation of indole and derivatives thereof by reacting
~, an aniline with a 1,2-glycol in the presence of a copper-
containing catalyst.
.j
2) Description of the PrioT Art
i ll In the prio~ art, indole derivatives have long
been prepared by the well-known Fischer indole synthesis in
which phenylhydrazine is reacted with a compound having an
aldehyde group. If the aldehyde compo~und is other than
acetaldehyde, the aforesaid Fischer indole synthesis can be
I , ,
.
~L~5~7
'
applied to obtain indole derivatives in good yield. However~
if the aldehyde compound is acetaldehyde, no reaction that
yields indole has been believed to take place. In order to
overcome this disadvantage, there has recently been proposed
an improved process which comprises reacting phenylhydrazine
with acetaldehyde at an elevated temperature of from 300
to 400C in the presence of an alumina catalyst (Japanese
Patent Laid-Open No. 76864/'73).
This process surely permits the reaction to pro-
ceed and brings about the formation of indole J but fails to
give a satisfactory yield. Moreover, it is greatly dis-
advantageous in that the catalyst has so short a life as to
become totally inacti~e after 0.5-1 hour's use.
Indole can also be prepared by another process
which comprises reacting o-toluidine with -formic acid to
form o-methyl-N-formylaniline and then fusing it together
with potassium hydroxide. However, it is usually impossible
to selectively prèpare o-toluidine that is used as the
starting material in this process. That is, the ~-isomer
is always formed in an amount equal to or greater than that
of the o-isomer. Thus, treatment of the isomer formed as
a by-product poses a serious problem in the case of indus-
trial production. Moreover, the handling of solids as in
alkali fusion is troublesome. For these reasons, the
aforesaîd process cannot be regarded as suitable for indus-
trial purposes.
Furthermore~ a number of attempts have been made
to synthesize indole from N~ -hydroxyethylamine, but none
,
,
,, .
72~
o them are satisfactory from an industrial point of view.
For example, a process which comprises effecting the
; reaction at 30UC in the presence of an aluminosilicate
catalyst [Zhur. Obschue. Khim., Vol. 24, pp. 671-678 (1954)]
gives only a very low yield of indole. A process which
comprises heating the reactant together with a molten mixed
salt consisting mainly of zinc chloride (Japanese Patent
Laid-Open No. 57968/'73) can give a fairly high yield of
indole. However, this process has the disadvantage of
requiring a complicated procedure, which makes it unsuitable
~I for industrial purposes.
l~ ~s described above, a number of processes for the
¦ synthesis of indole and derivatives thereof have been
; proposed. However, many of them aLre disadvantageous in that
amaunts of by-products are -formed, expensive compounds are
used as the starting materials, and/or lengthy and compli-
cated procedures are required to obtain the desired products.
Summary of the Invention
; It is an object of the present invention to pro-
; ,
vide a one-step process for the highly selective preparation
of indole and derivatives thereof by using inexpensive
compounds as the starting materials.
An aspect of the invention is as follows:
A process for the preparation of an indole which
comprises reacting an aniline of the general formula ~I)
NH2
~ R (I)
where R represents a hydrogen atom, halogen atom, hydroxyl
group, alkyi group or alkoxy group, with a 1,2-glycol selected
from the group consisting of ethylene glycol, propylene
glycol, 1,2-butanediol, 1,2~4-butanetriol, glycerol, 2,3-
butanediol and diethylene glycol in the presence o~ a
catalyst containing metallic copper and/or copper oxide, in
the liquid phase at a temperature in the range of from 200C
to 500C, thereby forming the indole.
This reaction can be carried out both in the
-3a-
, ~ .
llS07z9
ll
ll
liquid phase and in the vapor phase. By way of example, the
process of the present invention makes it possible to obtain
indole by reacting aniline with ethylene glycol and to
obtain 5-methylindole by reacting ~-toluidine with ethylene
glycol.
Thus, the process of the present invention has a
number of advantages. First, the anilines and 1,2-glycols
which can be used as the starting materials are very in-
expensive. Secondly, the preparation of indole or a deriv-
ative thereof from the starting materials can be achieved
in a single step. Thirdly, by-products are scarcely formed
and a very high selectivity is attained, so that indole or
a derivative thereof can be obtained in highly pure form.
I
i Detalled DescTiption of the Invention
The aniline used in the process of the present
invention is a compound of the general formula
` NH2 `
I ~ R (I)
¦l where R represents a hydrogen atom, halogen atom, hydroxyl
group, alkyl group OT alkoxy group. Specific examples
thereof are aniline, o-toluidine, _-toluidine, ~-toluidine,
o-haloanilines, ~-haloanilines, m-haloanilines, o-aminophenol,¦
_-aminophenol, p-aminophenol, o-anisidine, _-anisidine,
p-anisidine and the like.
The 1,2-glycol used in the process of the present
invention is a member selected from the group consisting of
- 4 -
,' I
:` I
~5a~2~
`
ethylene glycol, propylene glycol, 1,2-butanediol, 1,2,4-
butanetriol, glycerol, 2,3-butanediol, diethylene glycol
and the like.
¦ The process of the present invention is carried
out in the presence of a catalyst. The catalyst used
therein is a copper-containing catalyst. That is, the
¦ catalyst contains metallic copper and/or copper oxide and,
optionally, one or more other compounds.
More specifically, the catalysts which can be
used in the process of the present invention are ones
comprising metallic copper and/or copper oxide in such a
form as powder, granules, masses, flakes, shaped pieces or
the like; metallic copper ancL/or copper oxide supported on
a carrier; a mixture of metallic copper and/or copper oxide
and one or more other compounds; or such a mixture supported
on a carrier.
I'
The other compounds which can be used in combi-
nation with metallic copper and/or copper oxide include the
halides, nitrates, sulfates, carbonates, organic acid
salts, oxides, hydroxides and the like of lithium, sodium,
potassium, magnesium, calcium, strontium, barium, copper, I
silver, meTcuTy, zinc, aluminum, tin, iron3 cobalt, nickel, I
chromium, manganese, lead, molybdenum and the like; these
metals in the elemental state; and the like.
The above-described catalysts can be prepared,
for example, by the soaking method in which a carrieT is
soaked in an aqueous solution of a water-soluble copper
salt, dried and then subjected to thermal decomposition.
1 ,
1,
- 5 -
; I
~ 5~ 9
Alternatively, they can also be prepared by the coprecipita-
tion method. For example, an alkali is added to a stirred
¦ aqueous solution of copper nitrate, magnesium nitrate,
j, manganese nitrate and the like to coprecipitate copper,
magnesium, manganese and the like. The precipitate so
formed is separated by filtration, washed, dried and then
calcined. The metal salts should be used in such amounts
as to give the above-defined composition. Preferably, the
I precipitate is dried at room temperature for several to 24
l~ hours, at temperatures of from 100 to 200C for several
hours, or at temperatures of from 350 to 550C for several
hours. When dried at temperatures of from 100 to 250C,
the precipitate is preferabl~ pelletized prior to calcination.
As the carrier on which the catalytic substance
of the present invention (i.e., me~aliic copper and/or
copper oxide or a mixture of metallic copper andjor copper
oxide and one or more other compounds) is supported, any
materials that arè in common use for supported catalysts can
be used. However, diatomaceous earth, pumice, titania,
silica-alumina, alumina, magnesia, silica gel, activated
carbon, activated clay, asbestos and the like are used in
typical cases.
I Supported catalysts can be prepared by supporting
the above-described catalytic substance on these carriers
¦¦ according to any conventional techniques. For example, they
are prepared by soaking a carrier in an aqueous solution of
a copper salt and, if necessary, other metal salts, adding
sodium hydroxide thereto with stirring, and then drying the
ll l
-- 6
:
72~
carrier until the water included therein is evaporated
completely. No particular limitation is placed on the amount
f catalytic substance supported on the carrier. Usually,
depending on the type of carrier used, any suitable amount
(for example, from 1 to 50%) of catalytic substance may be
supported thereon.
Prior to the start of the reaction, the catalyst
is usually subjected to a reduction treatment according to
any conventional procedure. This is accomplished, for
example, by heating the catalyst bed slowly with a mixture
of hydrogen gas and nitrogen gas flowing therethrough and
then keeping it at a temperature of from 200 to 300C for
several hours.
~ lthough the process of the present invention can
be carried out in the vapor phase, the licluid phase or a
mixed vapor-liquid phase, it is usually carried out in the
vapor phase~ Where the process of the present invention is
carried out in thè vapor phase, a fixed-bed, fluidized-bed
or moving-bed reactor can be used to effect the reaction by
heating the vapors of an aniline and a 1,2-glycol in the
presence of a catalyst. In this case, various inert gaseous
substances may coexist as diluents for the vapors of the
starting materials. The useful inert gaseous substances
include, for example, nitrogen gas, carbon dioxide gas,
water vapor, and the vapors of compounds that are inert to
this reaction. Moreover~ hydrogen gas or a hydrogen-contain-
ing gas may be used as a diluent.
The use of hydrogen gas or a hydrogen-containing
Ii ,
l - 7 -
I
~ ~ 5i~72~
., .
gas is especially suitable for the purpose of maintaining
I the activity of the catalyst.
j Similarly, owing to its ability to suppress the
decomposition of the 1,2-glycol over the catalyst, the use
of water vapor is suitable for the purpose of maintaining
the activity of the catalyst and enhancing the yield of the
I desired product.
- l The amounts of aniline and 1,2-glycol fed to the
reactor should be such that from 0.01 to 5 moles and prefer-
ably from 0.05 to 2 moles of the 1,2-glycol is provided for
each mole of the aniline. I:E the amounts are outside this
range, a reduction in yield will be caused and/or large
amounts of by-products will be formed. These starting
materials are fed, after being vaporized in advance or
directly in liquid form, to the reactor at a liquid space
` velocity o~ from 0.01 to 5 liters/liter of the catalyst/hour.
; The process of the present invention is carried
~` ~ out at a reaction temperature in the range of from 200 to
600C and preferably from 250 to 500C. If the reaction
temperature is lower than 200C, the reaction can hardly
proceed, while if it is higher than 600C, undesirably large
amounts of by-produc*s will be formed.
The reaction pressure may be superatmospheric,
atmospheric or subatmospheric.
Where the process of the present invention is
¦ carried out in the liquid phase or a mixed vapor-liquid
phase, the reaction is effected by heating a mixture of an
l aniline and a 1,2-glycol in the presence of at least one
.1,
. . ;
,
~15~ 9
Il ,
" ~
¦l member selected from the above-described catalysts. In
~I this case, various inert gaseous substances and/or solvents
¦ may coexist as diluents -for the starting materials. The
¦ useful inert gaseous substances include, for example,
nitrogen gas, carbon dioxide gas, water vapor and the vapors
of compounds that are inert to this reaction. The useful
solvents include, for example, benzene, toluene, xylene,
methanol, ethanol, isopropanol, dioxane, dimethylformamide,
~ dimethyl sulfoxide, pyridine, N-methylpyrrolidone, tri-
,l methylamine, diethylamine, triethylamine, tripropylamine,
j tTibutylamine, diphenylamine, triphenylamine and other
I organic solvents.
I IIn the case of liquid-phase reaction, the process
I ~of the present invention can be carried out in a fixed-bed7
fluidized-bed or moving-bed reactor or in a rotary or con-
tinuous reactor for liquid-phase reactions. However, no
particular limitation is placed on the type of reactor used.
The amounts of aniline and 1,2-glycol used as the
starting materials for this reaction should be such that
from 0.05 to 5 molès and preferably from 0.1 to 2 moles of
the 1,2-glycol is provlded for each mole of the aniline.
~ No particular limitation is placed on the amount
; Ijof catalyst used for this reaction. However, the catalyst
¦ is generally used in an amount of from 0.01 to 20 g and
preferably from 0.1 to lO g of the active component thereof
per mole of the aniline used as one of the starting materials.
The reaction temperature should be in the range of
from 200 to 500C and preferably from 250 to 400C. If
ll l
,1 9
.1 i.
.
the reaction temperature is low0r than 200Cs the reaction
can hardly proceed9 while if it is higher than 500C,
undesirably large amounts of by-products will be formed.
The reaction pressure may be superatmospheric or
, atmospheric.
In various embodiments of the present invention,
indole or a derivative thereof can readily be obtained in
pure form by isolating it from the reaction product accord-
ing to any conventional technique such as distillation.
The present invention is further illustrated by
the following examples.
Example 1
Il ~
A 25-mm flow reactor made of Pyrex glass was packed
with 50 m~ of copper oxide in granular form. The front end
of this Teactor was connected with a feed inlet pipe and a
,-` gas inlet pipe to form a feed vaporization zone, while the
rear end thereof was connected with a receiver by way of an
air-cooling zone. After the copper oxide within the reactor
was reduced by passing therethrough hydrogen gas at 200C
for 1 hour, the internal temperature of the reactor was
kept at 300C. Then, a mixture consisting of 93.1 g ~1 mole)
il of aniline and 6.2 g (0.1 mole) of ethylene glycol was
introduced thereinto through the feed lnlet pipe at a liquid
space velocity of 0.1 litsr/liter of the catalyst/hour. At
the same time, nitrogen gas at atmospheric pressure was
passed therethrough in an amount of 10 moles per mole of
! the aniline used as one of the starting materials. The
,
^~c/e /J~J~r,~
- 1 0
,
~15~
! reaction product withdrawn from the reactor, condensed and
-i collected in the receiver was analyzed by gas chromatography.
Thus, it was found that a yield of 8.1 g of indole was
obtained. The conversion and selectivity based on the
ethylene glycol were 76.7% and 90.3%, respectively. This
indicates that by-products were formed in very small amounts.
Example 2
Using a reactor similar to that of Example 1,
reaction was carried out in the same manner as described in
Example 1 except that a catalyst comprising 20% by weight
of copper oxide supported on diatomaceous earth was used in
place of the unsupported copper oxide catalyst. As a result,
a yield of 7.5 g of indole was obtained. The conversion and
I selectivity based on the ethylene glycol were 73.2% and
I 87.6%, respectively.
jl
Example 3
I!
Using a reactor similar to that of Example 1,
li reaction was carried out in the same manner as described in
il
Example 1 except that a catalyst comprising 10% by weight
of copper oxide supported on granular activated carbon was
I used in place of the unsupported copper oxide catalyst. I
¦ As a result, a yield of 8.5 g of indole was obtained. The
con~ersion and selectivity based on the ethylene glycol
were 78.1% and 87.2%, respectively.
- 11 -
, '
I 1~5~7~9
Example 4
Using a reactor similar to that of Example 1,
¦ reaction was carried out in the same manner as described in '~
Example l except that a CuO-ZnO catalyst ~containing 10
Il mole % of ZnO) was used in place of the unsupported copper
¦¦ oxide catalyst. As a result, a yield of 8.6 g of indole was
obtained. The conversion and selectivity based on the
ethylene glycol were 80.3% and 91.2%, respectively.
,1 ,
Example 5
,i
1~ Using a reactor similar to that of Example 1,
reaction was carried out in the same manner as described in
¦ Example 1 except that a CuO-Cr2O3 catalyst (containing 20
mole % of Cr2O3) was used in place of the unsupported copper
oxide catalyst. As a result, a yie-d of 7.8 g of indole was
obtained. The conversion and selectivity based on the
ethylene glycol were 80.5% and 82.8%, respectively.
~ I
Example 6
' Using a reactor similar to that of Example 1,
,il reaction was carried out in the same manner as described in
Example 1 except that a CuO-MgO-MnO2 catalyst (containing
10 mole % of MgO and 10 mole % of MnO2) was used in place
Il of the unsupported copper oxide catalyst. As a result, a
I yield of 9.2 g of indole was obtained. The con~ersion and
,, selectivity based on the ethylene glycol were 85.2% and
1 92.1%, respectively.
:1 !
.
- 12 -
1, ,
~, Si~72~
~i :
Example 7
Using a reactor similar to that of Example 1,
reaction was carried out in the same manner as described
in Example 1 except that the Raney copper catalyst which
had been expanded and washed with water was used in place
of the unsupported copper oxide catalyst. As a result, a
yield of 6.4 g of indole was obtained. The conversion and
selectivity based on the ethylene glycol were 63.6% and
86.3%, respectively.
Example 8
Reaction was carried out in the same manner as
described in Example 1 except that 107 g ~1 mole) of ~-
¦ toluidine was used in place of the aniline. As a result,a yield o 2.3 g oE 5-methylindole was obtained. The
conversion and selectivity based on the ethylene glycol
were 24.2% and 73.5%, respectively.
. .
Example 9
~~ Reaction was carried out in the same manner as
I ,1 described in Example 1 except that 123 g ~1 mole) of
,1 ,
~-anisidine was used in place of the aniline. As a result,
a yield of 1.5 g of 5-methoxyindole was obtained. The
conversion and selectivity based on the ethylene glycol
were 14.6% and 70.3%, respectively.
~I ;
.i
,
~ - 13 -
.
1 ,
