Note: Descriptions are shown in the official language in which they were submitted.
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This invention relates to a novel process for
preparing benzyl alcohol derivatives of the formula:
OH
HO ~ NH CH2 2~oc 3
The above compounds [I] have advantageous properties.
For example, ~-(3,4-dimethoxyphenethylaminomethyl)-2-
hydroxybenzyl alcohol has an excellent blood sugar lowering
activity, and ~-(3,4-dimethoxyphenethylaminomethyl)-4-
hydroxybenzyl alcohol has an excellent cardiotonic
activity, and hence, these compounds are useful as
medicines.
It is known that the benzyl alcohol derivatives [I]
can be prepared by various methods. For example, U.S.
Patent 4,032,575 discloses that the compound [I] can be
prepared by the steps of condensing an ~-halo-monobenzyl-
oxyacetophenone (A) with 3,4-dimethoxyphenethylamine (B)
to give an ~-(3,4-dimethoxyphenethylamino)monobenzyloxy-
acetophenone (C), optionally reducing the compound (C) to
give an ~-(3,4-dimethoxyphenethylaminoethyl)-monobenzyloxy-
benzyl alcohol (D), and then subjecting the compound (C)
or (D) to catalytic hydrogenation. However, the method
disclosed in this U.S. Patent has the drawbacks that the
yield of the condensation product (C) decreases unless
the valuable starting amine (B) is used in an excess
amount, since the condensation product (C) is unstable and
susceptible to self-condensation or further phenacylation;
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and that the use of an excess amount of the amine does not
necessarily result in high yield.
As a result of investigations made by the present
inventors, it has now been found that, when one of the
starting materials, i.e. the 3,4-dimethoxyphenethylamine
derivative, is used after protecting the amino group, the
reaction can proceed without undesirable side reactions
and therefore the desired compounds [I~ can be prepared
in high yield and purity.
According to the present invention, the desired
compounds [I] can be prepared by subjecting an ~-halogen-
acetophenone derivative [IIl and a 3,4-dimethoxyphenethyl-
amine derivative [III] to a condensation reaction to give
an ~-(3,4-dimethoxyphenethylamino)acetophenone derivative
[IV] and subjecting the resulting compound to catalytic
hydrogenation either directly or after converting the
compound [IV] to an ~-3,4-dimethoxyphenethylaminomethyl)-
benzyl alcohol derivative [V] by treating it with a
reducing agent, as shown by the following reaction scheme:
o
R O ~ XC330 ~ NH_R2
[II] \~ ~ [III]
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Rl ~J N_CH2_CH2_~--OOCH3
[IV]
OH
Rl ~ N-cH2-cR2 ~ oC33
[v]
[I]
wherein Rl is a hydroxy group-protecting group which is
removable by catalytic hydrogenation, R2 is an amino
group-protecting group which is removable by catalytic
hydrogenation, and X is a halogen atom.
In the above formula [I~] and [III], the group R
includes, for example, aralkyl groups (e.g. benzyl),
,.,
aralkyloxycarbonyl groups (e.g. benzyloxycarbonyl or
p-methoxybenzyloxycarbonyl), and the like. A suitable
example of the group Rl is benzyl. On the other hand,
the group R2 includes, for example, aralkyloxycarbonyl
groups (e.g. benzyloxycarbonyl or p-methoxybenzyloxy-
carbonyl), aralkyl groups (e.g. benzyl or triphenylmethyl),
and the like. Suitable examples of the group R2 are
benzyl and benzyloxycarbonyl.
The process of the present invention is explained in
more detail with reference to the above reaction steps as
follows:
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[II] + [III] ~ [IV]
The condensation reaction of the ~-halogenoacetophenone
derivative [II] and the 3,4-dimethoxyphenethylamine deriva-
tive [III] is preferably carried out in an appropriate
solvent in the presence or absence of an acid acceptor.
Suitable examples of the acid acceptor are organic bases,
e.g. pyridine or triethylamine, and inorganic bases, e.g.
potassium carbonate or sodium hydroxide. When the organic
bases are used in an excess amount as the acid acceptor,
additional solvent is not required. However, examples of
appropriate solvents are lower alkanols (e.g. methanol or
ethanol), acetone, dimethylformamide, dimethylsulfoxide,
tetrahydrofuran, methylene chloride, chloroform, and the
like. The reaction proceeds readily at a temperature of
0 to 100C, preferably l5 to 50C.
[IV] ~[V]
The reduction of the resultant ~-(3,4-dimethoxyphen-
ethylamino)acetophenone derivative [IV] is carried out by
treating it with a reducing agent in a suitable solvent.
Suitable examples of the reducing agent are alkali metal
borohydrides (e.g. sodium borohydride, or lithium boro-
hydride), lithium aluminum hydride and diborane, prefer-
ably sodium borohydride. Examples of the solvent are lower
alkanols (e.g. methanol or ethanol), ether, tetrahydrofuran
and dioxane which are inert solvent. The reaction proceeds
readily at a temperature of 0 to 80C, preferably 0 to 25C.
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[IV]~ [I] and [V] ~[I]
The catalytic hydrogenation of the ~-(3,4-dimethoxyphen-
ethylamino)acetophenone derivative [IV] and the ~-(3,4-
dimethoxyphenethylaminomethyl)benzyl alcohol derivative
[V] obtained above can be carried out by the conventional
method, that is, by dissolving the compound [IV] (or [V]) or
a salt thereof in an appropriate solvent, and shaking the
mixture under a stream of hydrogen or stirring the mixture
under hydrogen pressure in the presence of a catalyst, by
which the protecting groups can readily be removed from the
compounds. Suitable examples of the catalyst are platinum
or palladium catalysts, e.g. platinum, platinum oxide,
palladium black, palladium-carbon colloidal palladium, and
the like. Suitable examples of the solvent are lower
alkanols (e.g. methanol or ethanol), water, acetic acid, and
the like. The reaction proceeds readily at a temperature of
0 to 50C and under hydrogen pressure of 1 to 5 kg/cm2.
The desired compounds [I] prepared according to the above
procedure can readily be isolated from the reaction mixture
in the usual manner, for instance, by filtering the reaction
mixture to remove the catalyst, concentrating the filtrate
under reduced pressure, and crystallizing the resulting
residue from an appropriate solvent. Optionally, the crys-
talline thus obtained is treated with an acid in the usual
manner to obtain the desired compounds [I] in the form of a
salt with an acid.
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The present invention is illustrated by the following
Examples but is not limited thereto.
Example 1
(1) ~-Bromo-2-benzyloxyacetophenone (1.53 g), N-benzyl-3,
4-dimethoxyphenethylamine (1.50 g) and triethylamine (1.11
g) were dissolved in 15 ml of dimethylformamide, and the
mixture was stirred at room temperature for 7 hours. The
reaction mixture was poured into ice-water and extracted with
ethyl acetate. The extract was washed with 10 ~ hydrochloric
acid, saline solution and aqueous sodium bicarbonate succes-
sively and further washed with saline solution, and then
dried and concentrated under reduced pressure to give oily-N-
benzyl-~-(3,4-dimethoxyphenethylamino)-2-benzyloxyacetophenone
(2.2 g~ 88.8 ~).
IR v lcmq-l 1670
Mass m/e : 495 (M )
NMR (CDC13,~ ): 3.82 (6H, s, OCH3), 5.05 (2H, s),
5.15 (2H, s)
This product was converted into 1/2 oxalate in the
usual manner, and recrystallized from methanol to give
colorless needles, m.p. 213 - 215C (decomp.).
(2) N-Benzyl-~-(3,4-dimethoxyphenethylamino)-2-benzyl-
oxyacetophenone (2.0 g) obtained in (1) was dissolved in
40 ml of methanol and sodium borohydride (1.2 9) was added
in portions to the solution, and the mixture was stirred
under ice-cooling for 4 hours. The mixture was poured
B
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into ice-water and extracted with ethyl acetate. The
extract was washed with water, dried and then evaporated
to give N-benzyl-~-(3,4-dimethoxyphenethylaminomethyl)-2-
benzyloxybènzyl alcohol (2.0 g) as an oily substance in
quantitative yield.
IR vliq-l: 3480
cm
Mass m/e : 497 (M+), 284 (base)
NMR (CDC13, ~): 3.3 (lH, bs., OH), 3.74 (3H, s, OCH3),
3.80 (3H, s, OCH3), 5.02 (2H, s,
OCH2pH), 5.0 - 5.3 (lH,>~H ), 6.5 7.7
(17H, aromatic H)
(3) Crude N-benzyl-~-(3,4-dimethoxyphenethylamino-
methyl)-2-benzyloxybenzyl alcohol (1.9 g) obtained in (2)
was dissolved in 40 ml of methanol and subjected to cata-
lytic hydrogenation with 10 % palladium carbon (500 mg) in
hydrogen gas stream under atmospheric pressure. After the
reaction, the catalyst was removed by filtration. The
filtrate was concentrated under reduced pressure to give
~-(3,4-dimethoxyphenethylaminomethyl)-2-hydroxy benzyl
alcohol (1.1 g) as an oily substance. After converting the
resultant oil into its succinate, the salt was recrystal-
lized from methanol/ether to give crystalline ~-(3,4-di-
methoxyphenethylaminomethyl)-2-hydroxybenzyl alcohol
succinate (1.33 g), m.p. 142 - 143C.
The hydrochloride of this product had a m.p. of 141 -
143C (recrystallized from ethanol/ether).
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Example 2
N-Benzyl-~-(3,4-dimethoxyphenethylamino)-2-benzyloxy-
acetophenone (600 mg), which was prepared in the same
manner as described in Example 1 - (1), was dissolved in
30 ml of methanol and subjected to catalytic hydrogenation
with 10 % palladium carbon (300 mg) until the stoichio-
metric amount of hydrogen was absorbed. The reaction
mixture was treated in the same manner as described in
Example 1 - (3), whereby ~-(3,4-dimethoxyphenethylamino-
methyl)-2-hydroxybenzyl alcohol succinate (280 mg) was
obtained as colorless crystals, m.p. 142 - 143C.
The hydrochloride of this product had a m.p. of 141 -
143C.
The product was identified with the standard specimen
by thin layer chromatography and a mixed melting point
test.
Example 3
(1) ~-Chloro-4-benzyloxyacetophenone (2.35 9),
N-benzyl-3,4-dimethoxyphenethylamine (2.7 9) and triethyl-
amine (2.0 g) was dissolved in 50 ml of ethanol and the
mixture was refluxed for 18 hours. The reaction mixture
was concentrated under the reduced pressure. The obtained
residue was purified by silica gel chromatography (solvent;
ether : hexane = 1 : 1), whereby N-benzyl-~-(3,4-
dimethoxyphenethylamino)-4-benzyloxyacetophenone (3.0 g,
60.6 %) was obtained as an oily substance.
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g
After converting the resultant oil to crystalline 1/2
oxalate, this salt was recrystallized from methanol to
give colorless needles, m.p. 122 - 125C.
IR v NcUm-~ : 1695, 1600
Mass m/e : 495 (M )
NMR (CDC13,~; 3.77 (3H, s, OCH3), 3.82 (3H, s, OCH3),
4.46 (2H, s), 4.63 (2H, s), 5.12 (2H, s,
OCH2ph )
(2) N-Benzyl-~-(3,4-dimethoxyphenethylamino)-4-benzyl-
oxyacetophenone.l/2 oxalate (1.3 g) obtained in (1) was
dissolved in 50 ml of methanol, and sodium borohydride
(2.0 g) was added in portions to the solution under ice-
cooling and the mixture was stirred overnight. After
the reaction, the mixture was poured into ice-water and
extracted with ethyl acetate. The extract was washed with
water, dried and then evaporated to give N-benzyl-~-~3,4-
dimethoxyphenethylaminomethyl)-4-benzyloxybenzyl alcohol
(1.2 g) as a crude oil substance.
IR v lcm-l : 3440
Mass m/e : 497 (M+), 284 (base)
NMR (CDC13,~): 3.75 (6H, s, OCH3), 3.93 (lH, bs, OH),
4.57 (lH, t, J = 6Hz, XoHH)t 4.97 (2H, s,
OCH2ph), 6.5 - 7.5 (17H, aromatic H).
(3) N-benzyl-~-(3,4-dimethoxyphenethylaminomethyl)-4-
benzyloxybenzyl alcohol (1.2 g) obtained in (2) was
dissolved in 40 ml of methanol and subjected to catalytic
hydrogenation with 10 % palladium carbon (400 mg) in a
o
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hydrogen gas stream under atmospheric pressure. After
the reaction, the catalyst was removed by filtration.
The filtrate was concentrated under reduced pressure to
give a-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzyl
alcohol as an oily substance. The resultant oil was
dissolved in ethyl acetate and hydrogen chloride in ether
was added to the solution under ice-cooling. The precipit-
ating amorphous substance was recrystallized from ethanol/
ether to give ~-(3,4-dimethoxyphenethylaminomethyl)-4-
hydroxybenzyl alcohol hydrochloride (657 mg) as colorless
needles, m.p. 164 - 167C.
The product was identified with the standard specimen
by thin layer chromatography and a mixed melting point
test.
Example 4
N-Benzyl-a- (3,4-dimethoxyphenethylamino)-4-benzyloxy-
acetophenone (500 mg), which was prepared in the same
manner as described in Example 3 - (3) was dissolved in 30
ml of methanol and subjected to catalytic hydrogenation
with 10 % palladium carbon (250 mg) until the stoichio-
metric amount of hydrogen was absorbed. The reaction
mixture was treated in the same manner as described in
Example 3 - (3), whereby a-(3,4-dimethoxyphenethylamino-
methyl)-4-hydroxybenzyl alcohol hydrochloride (180 mg)
was obtained as colorless needles, m.p. 164 - 167C.
The product was identified with the standard specimen
by thin layer chromatography and a mixed melting point test.
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