FIELD OF THE INVENTION
The present invention relates to an industrially advantageous and high throughput process for the preparation of imidazole-4,5-dicarboxylate derivative, particularly dialkyl-2-propylimidazole-4,5-dicarboxylate of formula I, (Formula Removed)
wherein R represents a straight-chained or branched C1-C4 alkyl group
a key intermediate in the preparation of olmesartan and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Olmesartan is chemically known as 4-(1-hydroxy-1-methyl-ethyl)-2-propyl-1-[[2'-(lH-tetrazol-5-yl)[l, 1 '-biphenyl]-4-yl]methyl]-lH-imidazole-5 carboxylic acid, and has the following structural formula.
(Formula Removed)Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kinase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATi receptor in vascular smooth muscle.
Olmesartan and pharmaceutically acceptable salts thereof have been first disclosed in US Patent 5,616,599. Several methods for the synthesis of olmesartan are disclosed therein and in other patents such as US 7,345,072, US 2006/0148870, WO 2007/047838, JP 07053489, CN 1381453 etc. A number of the known synthetic routes to olmesartan proceed via the key intermediate, diethyl-2-propylimidazole-4,5-dicarboxylate. The process disclosed in US Patent 5,616,599 for the preparation of diethyl-2-propylimidazole-4,5-dicarboxylate involves the reaction of diaminomaleonitrile with trimethyl orthobutyrate in acetonitrile to form l-amino-2-./V-(1-methoxybutylidene) aminosuccinonitrile followed by refluxing in xylene to form 2-propylimidazole-4,5-dicarbonitrile which was purified with column chromatography. The dicarbonitrile derivative was hydrolysed with 6N hydrochloric acid to form the corresponding diacid derivative. The diacid derivative is then esterified using ethanol and dry hydrogen chloride gas to form diethyl-2-propylimidazole-4,5-dicarboxylate.
The process suffers from several drawbacks such as the use of costly solvent like acetonitrile and recovery of acetonitrile poses great problem on an industrial scale. Further, the hydrolysis of dicarbonitrile derivative is performed using 6N hydrochloric acid. On repeating the same experiment, we have found that the product obtained by this process is contaminated with following impurities:
(Formula Removed)Therefore, the process requires additional purification steps that implicate increased reaction times and higher production costs. The overall yield of 2-propylimidazole-4,5-dicarboxylic acid from trimethyl orthobutyrate is 40-45%, that is very low, thus making the process unattractive from industrial point of view. Besides this, the patent teaches the use of purification techniques like column chromatography which is a time-consuming and tedious process; especially for large samples; hence it is not suitable for large scale production
In addition to this, it is observed that the esterification reaction of the diacid derivative using dry hydrogen chloride gas in ethanol does not go to completion. The esterification reaction is highly prone to acid catalysed hydrolysis. In the above reaction, water is generated that may hydrolyze the esterified compound back to its corresponding acid which may cause incompletion of reaction. All these factors further results in low yields of final active pharmaceutical ingredient, olmesartan.
In an article 'Organic Preparations and Procedures International 2006, 38(4), 410-412' a process for the preparation of diethyl-2-propylimidazole-4,5-dicarboxylate is disclosed. The process comprises treatment of tartaric acid with butyraldehyde and aqueous ammonia to give 2-propylimidazole-4,5-dicarboxylic acid followed by esterification with ethanol in the presence of thionyl chloride to form diethyl 2-propylimidazole-4,5-dicarboxylate.The process involves the use of thionyl chloride during esterification, which is a toxic, corrosive and lachrymatory reagent, hence it is not advisable to use it on an industrial scale.
Japanese patent Application No. 2006143615 discloses the preparation of diethyl-2-propylimidazole-4,5-dicarboxylate by esterification of the corresponding acids with alcohols in the presence of chlorosulphonic acid. The above patent application teaches the use of chlorosulphonic acid which is a hazardous chemical and is extremely toxic to lungs, mucous membranes, which makes the process unattractive on industrial scale.
Chinese patent Application No. 1830966 A discloses the preparation of 2-propylimidazole-4,5-dicarboxylic acid by oxidation of 2-propyl benzimidazole using different oxidizing agents such as hydrogen peroxide, ozone etc., but we have observed less yield in our hands due to formation of several impurities during the oxidation step.
In view of the above, there is thus an obvious need to find an efficient and industrially advantageous process for the synthesis of imidazole-5-carboxylate derivative particularly dialkyl-2-propylimidazole-4,5-dicarboxylate of formula I and olmesartan which overcomes the problems associated with the prior art such as low yields, long reaction time, use of hazardous reagents, stringent reaction conditions and tedious purifications.
OBJECT OF THE INVENTION
One principle object of the invention is to provide an efficient, and industrially viable process for the preparation of imidazole-4,5-dicarboxylate derivative, particularly dialkyl-2-propylimidazole-4,5-dicarboxylate with reduced time cycle.
Another object of the present invention is to provide a process for the preparation of imidazole-4,5-dicarboxylate derivative in high yield and purity; wherein purification of intermediates by column chromatography is avoided.
Yet another object of the present invention provides a process for preparing pure imidazole-4,5-dicarboxylate derivative that offers an advantage to industrial processes since complicated separation and purification steps can be avoided and the expenditure on equipment can be reduced.
One another object of the present invention is to provide a process for the preparation of highly pure imidazole-4,5-dicarboxylate derivative, wherein the formation of impurities of formulae A and B is minimized.
SUMMARY OF THE INVENTION
The present invention relates to an efficient and industrially advantageous process for the preparation of imidazole-4,5-dicarboxylate derivative, particularly dialkyl-2-propylimidazole-4,5-dicarboxylate of formula I,
(Formula Removed)wherein R represents a straight-chained or branched C1-C4 alkyl group
comprising the steps of:
a. reacting diaminomaleonitrile with trialkyl orthobutyrate in the presence of an acid in a suitable solvent to form 2-propylimidazole-4,5-dicarbonitrile of formula II;
(Formula Removed)b. hydrolyzing 2-propylimidazole-4,5-dicarbonitrile of formula II in the presence of
both an inorganic acid and an organic acid to form 2-propylimidazole-4,5-
dicarboxylic acid of formula III; and
(Formula Removed)c. esterifying compound of formula III in a suitable alcoholic solvent in the presence
of mineral acid such as cone, sulfuric acid and a suitable water scavenger to form
compound of formula I.
The present invention further relates to a process for the preparation of dialkyl-2-propylimidazole-4,5-dicarboxylate of formula I,
(Formula Removed)wherein R represents a straight-chained or branched C1-C4 alkyl group
which comprises esterifying 2-propylimidazole-4,5-dicarboxylic acid of formula III in suitable alcoholic solvent in the presence of mineral acid such as cone, sulfuric acid and suitable water scavenger to form compound of formula I.
The present invention also relates to a process for the preparation of 2-propylimidazole-4,5-dicarbonitrile of formula II,
(Formula Removed)which comprises,
a. reacting diaminomaleonitrile with trialkyl orthobutyrate in the presence of an
acid in a suitable solvent to form compound of formula II; and
b. isolating compound of formula II.
The present invention further relates to a process for the preparation of 2-propylimidazole-4,5-dicarboxylic acid of formula III;
(Formula Removed)which comprises hydrolyzing 2-propylimidazole-4,5-dicarbonitrile of formula II in the presence of both an inorganic acid and an organic acid to form a compound of formula III.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, industrially advantageous and high throughput process for the preparation of imidazole-5-carboxylate derivative, particularly dialkyl-2-propylimidazole-4,5-dicarboxylate of formula I,
(Formula Removed)wherein R represents a straight-chained or branched C1-C4 alkyl group
which is useful in the preparation of olmesartan and pharmaceutically acceptable salts thereof.
According to one embodiment of the present invention, imidazole-4,5-dicarboxylate derivative, particularly dialkyl-2-propylimidazole-4,5-dicarboxylate of formula I is prepared by initially reacting diaminomaleonitrile with trialkyl orthobutyrate to form 2-propylimidazole-4,5-dicarbonitrile of formula II.
(Formula Removed)Typically the process involves reacting diaminomaleonitrile with trimethyl orthobutyrate in the presence of an acid in a suitable solvent at ambient temperature. The temperature of the reaction mass is then raised to the reflux temperature of the solvent for the time sufficient to form compound of formula II. Preferably, the reaction mixture is refluxed for 10-30 hours. The reaction completion is monitored by thin layer chromatography (TLC). The compound of formula II is then isolated from the reaction mass by the methods well known in art such as distillation, extraction, evaporation and the like. Preferably compound of formula II is isolated by distillation and extraction with suitable solvent like cyclohexane.
Solvent can be selected from aromatic hydrocarbons like toluene, xylene and the like. Acid can be selected from organic acids preferably acetic acid, formic acid, p-toluene, sulfonic acid and the like.
The present invention is advantageous as it provides a process for the preparation of 2-propylimidazole-4,5-dicarbonitrile of formula II from trimethyl orthobutyrate in one step without isolating the intermediates involved, if any, in solid state, thus reducing the time cycle of the reaction.
Another embodiment of the present invention provides a process for the hydrolysis of 2-propylimidazole-4,5-dicarbonitrile of formula II in the presence of both an inorganic acid and an organic acid to form 2-propylimidazole-4,5-dicarboxylic acid of formula III;
Typically, 2-propylimidazole-4,5-dicarbonitrile of formula II is dissolved in an inorganic acid and in a suitable organic acid and refluxed for the time sufficient to form compound of formula III. Preferably, the reaction mixture is refluxed for 15-30 hours. The reaction completion is monitored by thin layer chromatography (TLC). The compound of formula III is then isolated from the reaction mass by the methods well known in art such as distillation, extraction, evaporation and the like. Preferably the reaction mass is concentrated under vacuum, washed with water, filtered and dried to form 2-propylimidazole-4,5-dicarboxylic acid of formula III having purity greater than 98% area by HPLC.
Inorganic acid can be selected from hydrochloric acid and organic acid can be selected from acetic acid and the like.
The present invention thus provides better reaction medium for the hydrolysis of 2-propylimidazole-4,5-dicarbonitrile , hence minimizing the formation of impurities A and B to as low as below the detection limits.
Yet another embodiment of the present invention provides a process for the conversion of compound of formula III to dialkyl-2-propylimidazole-4,5-dicarboxylate of formula I by esterifying compound of formula III in a suitable alcoholic solvent in presence of mineral acid such as cone, sulfuric acid and suitable water scavenger.
As esterification reaction is to be performed in anhydrous conditions to avoid the presence of any starting material, it is advantageous to add a suitable water scavenger. In the process according to the invention, the orthoester of an organic acid acts as water scavenger and reacts with the water liberated in the esterification reaction to give alkyl ester and an alkanol; leaving the reaction in anhydrous conditions and shifting the reversible reaction equilibrium far to the right.
Typically, compound of formula III in a suitable alcoholic solvent is reacted with mineral acid such as cone, sulfuric acid in the presence of orthoester of an organic acid. Reaction is performed at reflux temperature of the solvent employed for a period of about 20-30 hours, preferably till reaction temperature (monitored by TLC). After completion of the reaction, the reaction mass is concentrated, the resulting residue is diluted with water, neutralized with sodium carbonate and extracted with ethyl acetate. The compound of formula I is isolated preferably by the methods well known in art such as distillation, extraction, evaporation and the like. Thereafter the residue is preferably triturated with suitable solvent like cyclohexane to obtain a

compound of formula III in high yield and purity. The product so obtained is also free from the following impurity:
(Formula Removed)wherein R represents a straight-chained or branched C1-C4 alkyl group
Solvent employed in the esterification reaction can be selected from, but not limited to C1-C4 alcohols, preferably ethanol or methanol can be employed. Orthoester of an organic acid can be selected from the group consisting of triethyl, trimethyl, tripropyl, triisopropyl, tributyl, triisobutyl, and triamyl orthoesters of organic acid selected from formic, acetic, oxalic, succinic and adipic acid; preferably triethyl orthoformate, triethyl orthoacetate, and the like and more preferably triethyl orthoformate is used.
2-Propylimidazole-4,5-dicarboxylate of formula I so formed can further be converted to olmesartan by the processes well known in the prior art.
Major advantages realized in the present invention are high yield and purity achieved by minimizing the impurity formation. No further purification is required, thus involving lesser number of steps and is hence time conserving
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow.
EXAMPLES
Preparation of 2-propylimidazole 4, 5-dicarboxylic acid Example 1:
To a stirred suspension of diaminomaleonitrile (50 g, 0.46 moles) in toluene (300 ml), acetic acid (20 ml) and trimethylortho butyrate (85.6 g, 0.58 moles) were slowly added at 25-30°C. The reaction mass was heated to reflux for 24 hours. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the solvent was distilled under vacuum at 50-60°C to give a crude product which was stirred with cyclohexane (150 ml) at 25-30°C for 1 hour. The solid product was filtered and dried to give 2-propylimidazole-4, 5-dicarbonitrile as brown coloured solid (65.0g), which was dissolved in cone, hydrochloric acid (260 ml) and acetic acid (260 ml). The solution was reflux for 22 hours and the progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mass was concentrated under vacuum to give solid product which was stirred with water (400 ml) for 1 hour, filtered and dried to give 65.0 g of title compound as light brown coloured solid (Yield:71% Purity: 98.5%). Example-2:
To a stirred suspension of diaminomaleonitrile (200 g, 1.85 moles) in toluene (1.2 L), acetic acid (80 ml) and trimethylortho butyrate (342 g, 2.3 moles) were slowly added at 25-30°C. The reaction mass was heated to reflux for 24 hours. The progress of reaction was monitored by thin layer chromatography. After the completion of reaction, the reaction mass was cooled to 60°C and the solvent was distilled under vacuum at 55-60°C to give crude product which was stirred with cyclohexane(600 ml) at 25-30°C for 1 hour. The solid product was filtered and dried to give 2-propylimidazole-4,5-dicarbonitrile as brown coloured solid (258 g), which was dissolved in cone, hydrochloric acid (1.03 L) and acetic acid (1.03 L). The solution was reflux for 22 hours. The progress of reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mass was concentrated
• under vacuum to give solid which was stirred with water (1.5 L) for 1 hour, filtered and dried to give 250 g of title compound as light brown coloured solid (Yield: 68% Purity: 98%).
Preparation of diethyl 2-propylimidazole 4.5-dicarboxylate Example-1:
To a stirred suspension of 2-propylimidazole-4,5-dicarboxylic acid (100 g) in ethanol (800 ml), cone, sulphuric acid (110 ml) and triethylortho formate (400 ml) were added and refluxed for 24 hours. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mass was concentrated. The resulting residue was diluted with demineralized water (600 ml) and neutralized with sodium carbonate (300 g).The reaction mass was extracted with ethyl acetate (2x400 ml).The combined organic layer was dried over sodium sulfate and distilled under reduced pressure to give crude product which was triturated with cyclohexane (300 ml) and filtered to give 105 g of the title compound (Yield: 82% Purity: 99.5%). Example-2:
To a stirred suspension of 2-propylimidazole 4,5-dicarboxylic acid (1.85 Kg) in ethanol (15.0 L), cone, sulphuric acid (2.0 L) and triethylortho formate (7.4 L) were added and refluxed for 24 hrs. The progress of the reaction was monitored by thin layer chromatography. After the completion of reaction, the reaction mass was concentrated and the resulting residue was diluted with demineralized water (11.1 L) and neutralized with sodium carbonate. The reaction mass was extracted with ethyl acetate (2x7.5 L).The combined organic layer was dried over sodium sulfate and distilled under reduced pressure to give crude product which was triturated with cyclohexane (5.5 L) and filtered to give 1.95 kg of title product (Yield: 82.%
Purity: 99.6 %).

WE CLAIM
1. A process for the preparation of imidazole-4,5-dicarboxylate derivative, particularly dialkyl-2-propylimidazole-4,5-dicarboxylate of formula I
(Formula Removed)
wherein R represents a straight-chained or branched C1-C4 alkyl group comprising the steps of:
a. reacting diaminomaleonitrile with trialkyl orthobutyrate in the presence of
an acid in a suitable solvent to form 2-propylimidazole-4,5-dicarbonitrile of
formula II;
(Formula Removed)
b. hydrolyzing 2-propylimidazole-4,5-dicarbonitrile of formula II in the
presence of both an inorganic acid and an organic acid to form 2-
propylimidazole-4,5-dicarboxylic acid of formula III; and
(Formula Removed)
c. esterifying compound of formula III in a suitable alcoholic solvent in the presence of a mineral acid and suitable water scavenger to form compound of formula I.
2. The process according to claim 1, wherein in step a, solvent is selected from
aromatic hydrocarbons like toluene or xylene.
3. The process according to claim 1, wherein in the step a, acid is selected from acetic
acid, formic acid, p-toluene sulfonic acid etc.
4. The process according to claim 1, wherein in the step b, an inorganic acid is selected from concentrated hydrochloric acid and an organic acid is selected acetic acid.
5. The process according to claim 1, wherein in step c, solvent is selected from C1-C4
alcohols; mineral acid is selected from cone, sulfuric acid and water scavenger is an orthoester of an organic acid and is selected from the group consisting of triethyl, trimethyl, tripropyl, triisopropyl, tributyl, triisobutyl, and triamyl orthoesters of formic, acetic, oxalic, succinic and adipic acid; such as triethyl orthoformate.
6. A process for the preparation of dialkyl-2-propylimidazole-4,5-dicarboxylate of
formula I,
(Formula Removed)
wherein R represents a straight-chained or branched C1-C4 alkyl group
comprising,
esterifying 2-propylimidazole-4,5-dicarboxylic acid of formula III in a suitable alcoholic solvent in the presence of mineral acid such as cone, sulfuric acid and a suitable water scavenger to form compound of formula I.
7. The process according to claim 6, wherein solvent is selected from C1-C4 alcohols and water scavenger is an orthoester of an organic acid and is selected from the group consisting of triethyl, trimethyl, tripropyl, triisopropyl, tributyl, triisobutyl, and triamyl orthoesters of formic, acetic, oxalic, succinic and adipic acid; such as triethyl orthoformate.
8. A process for the preparation of 2- propylimidazole-4,5-dicarbonitrile of formula II,
(Formula Removed)
comprises,
reacting diaminomaleonitrile with trimethyl orthobutyrate in the presence of an acid in a suitable solvent to form compound of formula II; and isolating compound of formula II.
9. The process according to claim 8, wherein solvent is selected from aromatic
hydrocarbons like toluene or xylene and acid is selected from acetic acid or p-toluene sulfonic acid.
10. A process for the preparation of 2-propylimidazole-4,5-dicarboxylic acid of formula III;
(Formula Removed)
comprises,
hydrolyzing 2-propylimidazole-4,5-dicarbonitrile of formula II in the presence of both an inorganic acid such as concentrated hydrochloric acid and an organic acid such as acetic acid to form compound of formula III.