Note: Descriptions are shown in the official language in which they were submitted.
he present invention relates to an improvement
in the method for producing an aye dimethoxyphenethyl--
amino)acetophenone derivative represented by the formula:
ROW NH '- CH2CH2 - OX 3
wherein R is a protective group for hydroxyl group,
or an acid addition salt thereof.
The compound (I) of the present invention is
useful as an intermediate in the synthesis of medicines.
For example, the compound (I) is useful as intermediates
in the synthesis of a-(3,4-dimethoxyphenethylaminomethyl)-
2-hydroxybenzyl alcohol which is a blood sugar-lowering
agent, and a- ( 3 9 4-dimethoxyphenethylaminomethyl)-4-
hydroxybenzyl alcohol which is a long-lasting cardiotonic
agent (US. Patent No. 4,032,575).
It is known that the compound (I) can be pro-
duped, for example, by condensation of a halogenoaceto-
phenone derivative of the formula:
R0 (II)
wherein X is a halogen atom and R is as defined above,
with 3,4-dimethoxyphenethylamine (III). In this method,
it is difficult to obtain the compound (I) in a good
yield if said method is carried out in the presence
of conventional organic or inorganic bases In order
to obtain the compound (I) in a high yield, therefore,
the large excess of the amine (III) must be used for
the reaction so that said amine serves as both the
starting material and the acid acceptor.
However, said method of carrying out the above-
mentioned condensation in the presence of the excess
of the amine (III) is still disadvantageous in that
(1) said amine (III) is so expensive that an additional
step for recovery of the amine becomes necessary; and
also that (2) it is accompanied with side reactions
such as further reaction of the resultant compound (I)
with the compound (II). Such side reactions may be
prevented by adding the compound (II) gradually to the
compound (III), but in this latter case, operators are
always exposed to danger during the reaction because
the compound (II) is irritant and corrosive.
An object of the present invention is to
provide an economical process for the industrial scale
production of the acetophenone derivative (I).
Another object of the invention is to provide a process
for preparing the acetophenone derivative (I) in a high
yield without side reactions or dangerous operations.
urethra objects of the present invention will be Papa-
rent from the following description and claims.
According to the present invention, the
-(3,4-dimethoxyphenethylamino)acetophenone derive-
live (I) is prepared by condensation of a halogen-
acetophenone derivative (II) with ~,4-dimethoxyphenethyl-
amine (III) in a two-phase solvent system of a non-
hydrophilic organic solvent and water in the presence
of an acid acceptor.
In the method of the present invention, any
groups which are removable by catalytic hydrogenation
or treatment with an acid can be used as the protective
group represented by the symbol R. examples of such
protective group include bouncily, benzyloxycarbonyl,
tert.-butyl, triphenylmethyl and the like. On the other
hand, suitable examples of the acid acceptor to be used
in the invention include an alkali metal hydroxide such
as sodium hydroxide or potassium hydroxide; an alkali
earth metal hydroxide such as calcium hydroxide; an
alkali metal carbonate such as sodium carbonate or
potassium carbonate; and an alkali metal bicarbonate
such as sodium bicarbonate or potassium bicarbonate.
As for the compounds of the formula (II) those wherein
X is By are preferable. It is preferred to use 1.1 to
moles of the acid acceptor per mole of the compound
IT
hey inert organic solvents which dissolve the
compound IT and which are immiscible with water can
be used as the non-hydrophilic organic solvent of the
invention. Preferred examples of such non-hydrophilic
:1 I
organic solvent are an aromatic hydrocarbon such as
Bunsen or Tulane; a halogenohydrocarbon such as
ethylene chloride or chloroform; and an ether such
as deathly ether or diisopropyl ether. The non-
hydrofoil organic solvent should be used in amount
sufficient to dissolve the compound (II). To be more
specific, for example, i-t is preferred to use 5 to 10
parts by volume of the non-hydrophilic organic solvent
per part by weight of the compound (II). On the other
hand, water should be used at least in an amount surf-
fishnet to dissolve the acid acceptor. o'er example,
it is preferred to use water in an amount of 2 parts by
weight per part by weight of the acid acceptor.
The condensation reaction of the compound (II)
with the compound (III) can be carried out, for employ
by dissolving the compound (III) in the two-phase solvent
system of the non-hydrophilic organic solvent and water,
and adding the compound (II) to the mixture. Alterna-
lively, said condensation reaction of the invention may
be carried out by dissolving the compound (II) in the
two-phase solvent, and adding the compound (III) thereto.
In both of these eases, it is preferred to use 1.2 to
2 moles of the compound (III) per mole of the compound
(II). It is also preferred to carry out the reaction
under stirring
he reaction proceeds smoothly at a temperature
of about 0C. to room temperature, preferably about 0C.
26
to about 10C. The reaction time is not critical
so far as the reaction is proceeded to a desired
extent. Generally it takes 10 - 60 minutes.
The acetophenone derivative (I) prepared
according to the present invention may be, if required,
converted into an acid addition salt thereof. Suitable
examples of the salt include inorganic acid addition
silts such as hydrochloride hydrobromide, per chlorate,
nitrate, sulfate or phosphate; and organic acid addition
salts such as acetate, preappoint, glycolate, lactate,
ascorbate, Malta, fumalate, malonate, succinate,
oxalate, citrate, methansulfonate, benzenesulfonate,
aminobenzoate, sulfaminate, aspartame, glutamate or
nicotinate.
After the reaction the compound (I) can be
isolated from the reaction mixture in any proper manner.
For example the organic layer containing the compound
(I) is separated and the solvent is removed by evapora-
lion to obtain the compound (I) as a residue which is
preferably converted into an addition salt.
As described herein before, the method of the
present invention is quite advantageous for an industrial
scale production of the compound (I). In the method of
the invention, for example, both of the unstable starting
materials (i.e. the compound (II) and (III) ) remain
dissolved in the organic solvent layer during the react
lion and the condensation of the compound (II) with the
26
amine (III) proceeds solely in said organic solvent
layer. In addition the compound (I) and its hydrogen
halide obtained by the condensation reaction are highly
soluble in the organic solvent but scarcely soluble
in water. Thus, in the method of the present invent
lion, side reactions such as decomposition of the come
pound (II) or dimeri~ation of the compound (I) which
may be brought about in the presence of the acid acceptor
can be prevented quite effectively because, during the
reaction of the invention, there is no substantial chance
of contact of the compound (I) or (II) with the acid
acceptor dissolved in water. Moreover, since there is
no need to use the expensive amine (III) as the acid
acceptor, its amount can be decreased to minimum amount,
i.e. an amount necessary for the condensation. This
necessarily means that it enables to carry out the con-
sensation reaction of the invention without further side
reactions such as dehydrative condensation (formation
of Showoff base) between the compound (I) and the amine
(III). Further, the compound (I) obtained during the
reaction forms a salt with hydrohalogenic acid produced
as a by-product, and, therefore, said condensation reaction
of the invention proceeds preferably without accompanying
diphenacylation reaction (i.e. the reaction between the
compound (I) and the starting compound (II)) even by
adding the amine (III) gradually to the two-phase solvent
system containing the compound (II). Consequently, the
method of the present invention is also advantageous
in terms of safety of operation because it can be
conducted by first dissolving the necessary amount of
the irritant and corrositive starting material, i.e.
the compound (II), all at once to a reactor.
Practical and presently-preferred embodiments
of the present invention are illustratively shown in the
following Examples.
Example
15.3 g of 2-benzyloxy-a-bromoacetophenone are
added to a mixture of 10.9 g of 3,4-dimethoxyphenethyl-
amine, 4 g of sodium hydroxide, 90 ml of Tulane and
20 ml of water at 5 to 7~., and the mixture is stirred
at the same temperature for one hour. The Tulane
layer is collected from the mixture, washed with water
and then dried. The Tulane layer is evaporated under
reduced pressure to remove solvent. The residue is
treated with ethanolic hydrogen chloride. 13.1 g of
a(3,4-dimethoxyphenethylamino)-2-benzyloxyacetophennone
hydrochloride are obtained. Yield : 60 %
Mop. 177 - 180C.
Example ?
18.1 g of 3,4-dimethoxyphenethylamine, 15.3 g
of 2-benzyloxy-a-bromoacetophenone, 4 g of sodium
hydroxide, 90 ml of Tulane and 20 ml of water are
treated in the same manner as described in Example 1
(reaction period: 20 minutes), whereby 16.6 g of
a-(3,4-dimethoxyphenethylamino)-2-benzyloxyaceto-
phenone hydrochloride are obtained. Yield: 75
Example 3
10~9 g of 3,4-dimethoxyphenethylamine, 15.3 g
of 4-benzyloxy-a-bromoacetophenone, 4 g of sodium
hydroxide, 90 ml of Tulane and 20 ml of water are
treated in the same manner as described in Example 1
(reaction period: 30 minutes), whereby 14.8 g of
aye3,4-dimethoxyphenethylamino)-4-benzyloxyacetophenoone
hydrochloride are obtained. Yield: 67
Mop. 193 - 198C.
Example 4
18.1 g of 3,4-dimethoxyphenethylamine, 15.3 g
of 4-benzyloxy-a-bromoacetophenone, 4 g of sodium hydroxide,
90 ml of Tulane and 20 ml of water are treated in the
same manner as described in Example 1 (reaction period:
10 minutes), whereby 17.1 g of a-(3,4-dimethoxyphenethyl-
amino)-4-benzyloxyacetophenone are obtained.
Yield: 77,5 %
Example 5
A solution of 3.62 g of 3,4-dimethoxyphenethyl-
amine in 5 ml of Bunsen is added to a mixture of 3.05 g
of 4-benzyloxy-a-bromoacetophenone, 0.44 g of sodium
hydroxide, 25 ml of Bunsen and 4 ml of water at 5 to
7C., and the mixture is stirred at the same temperature
for 35 minutes. The reaction mixture is treated in
the same manner as described in Example 1. 3.23 g of
a-(3,4-dimethoxyphenethylamino)-4-benzyloxyacetophhe none
hydrochloride are obtained. Yield: 73 %
` Example 6
3.0 g of 4-benzyloxy-a-bromoacetophenone are
added to a mixture of 3.62 g of 3,4-dimethoxyphenethyl-
amine, Owe g of sodium hydroxide, 30 ml of ethylene
chloride and 4 ml of water at 5 to 7C. The mixture is
stirred at the same temperature for I minutes. The react
lion mixture it treated in the same manner as described
in Example 1. 2.81 g of a-(3,4-dimethoxyphenethylamino)-
4-benzyloxyacetophenone hydrochloride are obtained.
Yield: 64 %
Example 7
a- ( 3,4-dimethoxyphenethylamino)-2 benzyloxy-
carbonyloxyacetophenone is prepared in the same manner
as described in Example 1 except that 2-benzyloxycarbo-
nyloxy-a-bromoacetophenone is used instead of 2-benzyloxy-
~-bromoacetophenone.
Example 8
a- ( 3,4-dimethoxyphenethylamino)-2-tert.-
butyloxyacetophenone is prepared in the tame manner as
described in Example 1 except that 2-tert.-butyloxy-~-
bromoacetophenone is used instead of 2-benzyloxy-a-bromo-
acetophenone.
.... 10
~xampl Q9
a- (3,4-dimethoxyphenethylamino)-4-triphenyl-
methyloxyacetophenone is prepared in the same manner
as described in Example 1 except that 4-triphenyl-
methyloxy-~-bromoacetophenone lo used instead of 2-
benzyloxy ~-bromoacetophenone.
Example 10
-(3,4-dimethoxyphenethylamino)-2-benzyloxy-
acetophenone is prepared in the same manner a described
in Example 1 except that potassium hydroxide is used
instead ox sodium hydroxide.
Example 11
a- ( 3,4-dimethoxyphenethylamino)-2-benzyloxy-
acetophenone is prepared in the same manner as described
in Example 1 except that calcium hydroxide is used
instead ox sodium hydroxide.
Example 12
-(3,4-dimethoxyphenethylamino)-Z-benzyloxy-
acetophenone is prepared in the same manner as described
in Example 1 except that sodium bicarbonate or potassium
bicarbonate is used instead of sodium hydroxide.
example 13
(3,4-dimethoxyphenethylamino)-2-benzyloxy-
acetophenone is prepared in the same manner as described
in Example 1 except that sodium carbonate or potassium
carbonate is used instead of sodium hydroxide.
Example 14
aye 9 4-dimethoxyphenethylamino)-2-benzyloxy-
acetophenone is prepared in the same manner as described
in Example 1 except that chloroform is used instead of
Tulane.
Exhume 15
a- ( 3,4-dimethoxyphenethylamino)-2-benzyloxy-
acetophenone is prepared in the same manner as described
in Example 1 except that deathly ether or diisopropyl
ether is used instead of Tulane.
