CA2190858C - Intermediate for preparing a pharmaceutically active compound - Google Patents
Intermediate for preparing a pharmaceutically active compound Download PDFInfo
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- CA2190858C CA2190858C CA002190858A CA2190858A CA2190858C CA 2190858 C CA2190858 C CA 2190858C CA 002190858 A CA002190858 A CA 002190858A CA 2190858 A CA2190858 A CA 2190858A CA 2190858 C CA2190858 C CA 2190858C
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- compound
- formula
- methyl
- imidazol
- butyl
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Abstract
This invention relates to a compound of formula (I) and hydrates, solvates, and salts thereof.
Description
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)-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-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+
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
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
N' H
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)-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-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+
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
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
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.
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.
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.
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.
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.
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.
Claims (2)
1. A compound of the formula (I):
or a hydrate, solvate, or salt thereof.
or a hydrate, solvate, or salt thereof.
2. A process for preparing a compound of the formula (I) or a hydrate, solvate, or salt thereof, as defined in claim 1, whicn process comprises reacting a compound of the formula (II):
with sodium bisulfite.
with sodium bisulfite.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24643194A | 1994-05-20 | 1994-05-20 | |
| US08/246,431 | 1994-05-20 | ||
| PCT/US1995/005664 WO1995032189A1 (en) | 1994-05-20 | 1995-05-04 | Intermediate for preparing a pharmaceutically active compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2190858A1 CA2190858A1 (en) | 1995-11-30 |
| CA2190858C true CA2190858C (en) | 2005-10-04 |
Family
ID=35395861
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002190858A Expired - Fee Related CA2190858C (en) | 1994-05-20 | 1995-05-04 | Intermediate for preparing a pharmaceutically active compound |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2190858C (en) |
-
1995
- 1995-05-04 CA CA002190858A patent/CA2190858C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2190858A1 (en) | 1995-11-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |