Note: Descriptions are shown in the official language in which they were submitted.
WO 95/32189 PCT/US95/05664
INTERMEDIATE FOR PREPARING A PHARMACEUTICALLY
AC'T'IVE COMPOUND
Field of the Invention
The present invention relates to the bisulfate addition compound of a key
intermediate useful in the preparation of an angiotensin II (AII) receptor
antagonist.
Background of the Invention
PCT Application WO 94/06776 published March 31, 1994 describes a
process for preparing 1-alkylaryl-2-alkyl-5-formylimidazoles which comprises
reacting a 2-halo-2-propenal-3-alkyl ether, such as 2-bromo-3-(1-methylethoxy)-
2-
propenal, with a N-(1-iminoallcyl)aminoalkylaryl compound, such as N-(1-
iminopentyl)-4-(aminomethyl)benzoic acid. In particular, the PCT application
details the preparation of 4-[(2-n-butyl-5-formyl-1H-imidazol-1-
yl)methyl]benzoic
acid, which is a key intermediate in the preparation of (E)-3-[2-n-butyl-1-{(4-
carboxyphenyl)methyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, a
highly potent All receptor antagonist (Weinstock, et al., ~. Med. Chem.,
34:1514-
1517 (1991)). Although the process described in PCT Application WO 94/06776
produces the key intermediate in high yield and high purity, the isolation of
said
intermediate involves a lengthy procedure consisting of multiple extractions,
a
slurry with montmorillonite K-10 clay, and a distillation/crystallization
sequence.
Thus, there is a need for an alternate method for the isolation of 4-[(2-n-
butyl-5-
formyl-1H-imidazol-1-yl)methyl]benzoic acid, particularly when preparing this
intermediate on a commercial scale for use in the synthesis of (E)-3-[2-n-
butyl-1-
{ (4-carboxyphenyl)methyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic
acid.
It has now been found that purified 4-[(2-n-butyl-5-formyl-1H-imidazol-1-
yl)methyl]benzoic acid can be obtained by converting the intermediate to its
bisulfate addition compound, recrystallizing the addition compound and then
reconverting said addition compound to 4-[(2-n-butyl-5-formyl-1H-imidazol-1-
yl)methyl]benzoic acid. Also, the bisulfate addition compound itself can be
used
directly in the preparation of ethyl (E)-3-[2-n-butyl-1-{(4-
carboxyphenyl)methyl-
1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate, which is the immediate
precursor to (E)-3-[2-n-butyl-1-{ (4-carboxyphenyl)methyl-1H-imidazol-5-yl]-2-
(2-
thienyl)methyl-2-propenoic acid. The ease of work-up and the efficiency of the
isolation process which makes use of the bisulfate addition compound of 4-[(2-
n-
-1-
WO 95/32189 ~ 1 ~ ~ ~ ~ ~ PCT/US95/05664
butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid is advantageous from a
commercial viewpoint.
Summary of the Invention
The present invention provides for a compound according to the formula (I):
OH
HOOC ~ ~
N ~ S03
N+
H (I)
and hydrates, solvates, and salts thereof.
This invention relates to a compound ofO a formula (I):
HOOC
N 503
N+
H
and hydrates, solvates, and salts thereof.
The spec compound of this invention is the bisulfate addition compound
of 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid, and hydrates,
solvates, and salts thereof.
Generally, the compound of formula (I) is prepared by reacting a compound
of formula (11):
with sodium bisulfate.
HO
CHO
N
N
-2-
WO 95/32189 ~ PCTIUS95105664
Specifically, the compound of the formula (1) is prepared by the method
described in Scheme I.
//~\~NH
1. THF/H20/K2C03
OH
NH-CHZ HOOC
2. HOAc -
O pH=6.0-6.5 N S03Na
i + ~ i!'~\ 1
3. NaHS03 N
HO
H (3)
(1) (2)
OH
HOOC
HCI, H20 - N DSO
3
N'
H
(4)
According to Scheme I, 4-[(2-n-butyl-S-formyl-1H-imidazol-1-
yl)methyl]benzoic acid is formed by reacting N-(1-iminopentyl)-4-
(aminomethyl)benzoic acid (formula (I) compound in Scheme I) with 2-bromo-3-
(1-methylethoxy~2-propenal (formula (2) compound in Scheme I) in the presence
of a base, for example, potassium carbonate. (See PGT Application WO
94/06776.)
The resulting 5-formyl imidazole compound (formula (II) compound), without
isolation, is then reacted with sodium bisulfate to yield the intermediate
sodium salt
of the bisulfate addition compound (formula (3) in Scheme I). Treatment of the
formula (3) compound with aqueous hydrochloric acid (pH 1.0-1.5) resulted in
the
formation of the formula (4), Scheme I, compound, which is also a formula (I)
compound. 4-[(2-n-Butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid may
then be regenerated by reacting the formula (4) Scheme (I) compound with a
mixture of water, acetic acid and hydrochloric acid under nitrogen.
The compound of formula (I) may exist in hydrated or solvated form. Any
and all such hydrates and solvates are included within the scope of this
invention.
Salts of the compound of formula (I), such as the formula (3) Scheme (I)
compound, may be prepared by known methods from inorganic bases, including
alkali metal and allcaline earth bases, for example, lithium, sodium and
potassium
hydroxides, bicarbonates, and carbonates, and organic bases, such as
triethylamine,
butylamine, piperazine, choline and diethanolamine.
-3-
WO 95/32189 ' PCT/US95/05664
Use of the compound of this invention provides a new method for isolating
and purifying a key intermediate in the synthesis of a potent angiotensin II
receptor
antagonist. This isolation/purification process via the formation of the
bisulfite
addition compound of 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic
acid allows for the production of the key intermediate in a simplified manner,
which
is particularly useful when preparing this intermediate on a commercial scale.
The invention is illustrated by the following example. The example is not
intended to limit the scope of this invention as defined hereinabove and as
claimed
hereinbelow.
Example 1
Synthesis of the bisulfate addition compound of 4-[(2-butyl-5-formyl-1H-
imidazol
1-yl)methyl]benzoic acid
N-(1-iminopentyl)-4-(aminomethyl)benzoic acid (80 mMol, 19.13 g @ 80
%), 2-bromo-3-(1-methylethoxy)-2-propenal (88 mMol, 18.9 g @ 90 %), potassium
carbonate ( 104 mMol, 14,42 g), tetrahydrofuran (90 mL) and water ( 10 mL) are
combined, stirred vigorously and refluxed under a nitrogen atmosphere. After 3
hours of reflux, additional amounts of 2-bromo-3-( 1-methylethoxy)-2-propenal
( 12
mMol, 2.6 g @ 90 %) and potassium carbonate ( 15 mMol, 2.1 g) are added. After
4.5 hours of reflux, additional amounts of 2-bromo-3-(1-methylethoxy)-2-
propenal
(6.0 mMol, 1.3 g @ 90 %) and potassium carbonate (7.5 mMol, 1.05 g) are added.
After 6 - 7 hours of reflux, the reaction is cooled to ambient temperature.
The
mixture is diluted with water (25 mL) and the pH is adjusted to 6.0 - 6.5 with
glacial
acetic acid (as needed). The neutralized reaction is diluted with tert-
butylmethyl
ether (90 mL). Sodium bisulfate (20 g) and sodium chloride (16 g) are added to
the
well stirred mixture. The mixture is cooled to 0 - 5° C, stirred for 2
hours and the
intermediate sodium salt of the bisulfate addition compound (formula (3)
compound
in Scheme I) is isolated via vacuum filtration. This intermediate salt is
dissolved in
water (275 mL) and the resultant solution is acidified to pH 1.0 - 1.5 with
hydrochloric acid. The resultant mixture is cooled to 3 - 7° C for 2 -
3 hours and the
desired bisulfate addition compound (formula (4) compound in Scheme I) is
isolated
via vacuum filtration as a white, water-wet solid in 70 % crude yield.
Recrystallization of this wet solid from glacial acetic acid (40 mL) at
90° C
produces the title compound as a white solid in 60070 (29.5 g) yield after
drying in
vacuo.
-4-
WO 95/32189 ' y. g ~ ~ 5 g PCT/US95/05664
IR(FT, KBr): 3600-3100, N-H and O-H (hydroxyl) stretch; 3300-2800, O-H
(acid) stretch; 3100-2800, -C-H and =C-H stretches; 2800-2400, NH+ stretch;
1708,
C=O (carboxylic acid) stretch; 1614, C=N and C=C stretches; 1250-1160, C-O and
O-H (hydroxyl) stretch, C-O (acid) stretch, and S02 stretch; 1040 and 1014, C-
O
and O-H (hydroxyl) stretch and S03- vibration (cm 1).
It is to be understood that the invention is not limited to the embodiment
illustrated hereinabove and the right to the illustrated embodiment and all
modifications coming within the scope of the following claim is reserved.
-5-
