Description:FORM 2

THE PATENTS ACT,
(39 OF 1970)
THE PATENT RULES, 2003.

COMPLETE SPECIFICATION
(SECTION 10 AND RULE 13)

AN IMPROVED PROCESS FOR PREPARATION OF “1H-IMIDAZOLE-4-CARBALDEHYDE” AND ITS PURIFICATION THEREOF

Suraj Laboratories Pvt Ltd
Raja Praasadamu, Plot No.6/A 6/B,
Masjid Banda, Kondapur,
Hyderabad, Telangana, INDIA-500084.

The following specification particularly describes the invention and the manner in which it is to be performed
AN IMPROVED PROCESS FOR PREPARATION OF “1H-IMIDAZOLE-4-CARBALDEHYDE” AND ITS PURIFICATION THEREOF

FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of 1H-imidazole-4-carbaldehyde of Formula-I. The invention further relates to purification of 1H-imidazole-4-carbaldehyde of Formula-I.

(Formula I)

BACKGROUND OF THE INVENTION:
1H-imidazole-4-carbaldehyde is an important chemical intermediate, with a wide range of market applications, mainly used in synthesis of Murexine and Detomidine Hydrochloride.
Organic Syntheses, Coll. Vol. 3, p.460 (1955); Vol. 24, p.64 (1944) discloses a process for preparation of (1H-imidazol-4-yl)methanol, which uses 95% fructose as a raw material and includes reaction with basic cupric carbonate, ammonia and formaldehyde. The process involves cleavage of copper imidazole complex by passing hydrogen sulfide into reaction mass. Hydrogen sulfide being a flammable and toxic material is not recommendable for handling on larger scales in pharmaceutical industry. The process also includes additional steps for purification of product by preparation of corresponding picrate and hydrochloride salts, which further made the process cumbersome and less economic at industrial scale. Our impugned invention achieves high purity and yields by avoiding the usage of toxic hydrogen sulfide and additional purification methods by a simple and improved process.
The synthetic process disclosed in Organic Letters (2003), 5(14), 2513-2515 for preparation of (1H-imidazol-4-yl)methanol involves usage of Thioacetamide for removal of copper as copper sulfide. The process involves additional operation of passing air into reaction mass. In addition, the process also suffers from disadvantage of purification of crude product by silica gel column chromatography, which limits its production on commercial scales. Our impugned invention succeeds in production of final product on large scales by avoiding additional gas passing operations and expensive chromatography techniques by a simple and easily reproducible improved process.
The process taught by prior art have a complex methodologies and drawbacks of using toxic materials and additional expensive purification procedures, which limits the large scale application of invention. The technical problem to be solved by the present invention is to overcome the above-mentioned defects in the prior art and provide a simple , energy economical, commercially reproducible process for preparation and purification of final product and the intermediates with high yield and purities.

SUMMARY OF THE INVENTION:
An embodiment of the present invention provides an improved process for the preparation of 1H-imidazole-4-carbaldehyde of Formula (I),

Formula I

Which comprises,
Step-a) reaction of fructose with basic cupric carbonate, ammonia and formaldehyde, followed by cleavage of copper-imidazole complex by using sodium dithionite to obtain crude (1H-imidazol-4-yl)methanol,
Step-b) purification of crude (1H-imidazol-4-yl)methanol obtained in step a),
Step-c) oxidation of (1H-imidazol-4-yl)methanol obtained in step b) to 1H-imidazole-4-carbaldehyde,
Step-d) purification of crude 1H-imidazole-4-carbaldehyde obtained in step c).
DETAILED DESCRIPTION OF THE INVENTION:

A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description. The present invention described below in conjunction with specific embodiments. The examples are only preferred embodiments of the present invention and are not intended to limit the present invention.
In a preferred embodiment, the below process illustrates a method for the preparation of 1H-imidazole-4-carbaldehyde of Formula (I) by Scheme-I.
Schematic representation of Scheme-I is depicted below:

Scheme-I
In aspects, conversion of fructose to crude (1H-imidazol-4-yl)methanol may carried out using basic copper carbonate, ammonia and formaldehyde in presence of a suitable solvent and at a suitable temperature. The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, ethanol, methanol, water and like or a mixture thereof. Specifically, the solvent may be water. The suitable temperature for the conversion is in range of 50°C to 100°C. Preferably, in range between 95-100°C. In aspects, the suitable reagent used for removal of copper from reaction mixture include but not limited to H2S, Thioacetamide and sodium dithionite and like or mixture thereof. Specifically, sodium dithionite.

In aspects, purification of crude (1H-imidazol-4-yl)methanol may be performed using suitable solvent. Solvents used for purification include but not limited to methanol, ethanol, isopropyl alcohol (IPA), toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, chloroform, diethyl ether, methyltertiarybutyl ether (MTBE), isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, acetone, THF, DMF, DMAc, hexane, heptane, pentane, water and like or a mixture thereof. Preferably, isopropyl alcohol (IPA).

In aspects, conversion of (1H-imidazol-4-yl)methanol into 1H-imidazole-4-carbaldehyde may carried out using suitable oxidizing reagent in presence of a suitable solvent or a mixture of solvents in an appropriate proportions and at a suitable temperature. The suitable reagent used for oxidation includes but not limited to manganese oxide (MnO2). The solvents used include but not limited to toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, dichloromethane, chloroform, isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, DMF, ethanol, methanol, water and like or a mixture thereof. Specifically, the solvent may be acetonitrile or methanol or mixture thereof. The suitable temperature for the conversion is in range of 40°C to 90°C. Preferably, in range between 80-90°C.
In aspects, purification of 1H-imidazole-4-carbaldehyde may be performed using suitable solvent. Solvents used for purification include but not limited to methanol, ethanol, isopropyl alcohol (IPA), toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dichloromethane, chloroform, diethyl ether, methyltertiarybutyl ether (MTBE), isopropyl ether, ethyl acetate, isopropyl acetate, acetonitrile, acetone, THF, DMF, DMAc, hexane, heptane, pentane, water and like or a mixture thereof. Preferably, isopropyl alcohol (IPA).

The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.

Examples:
Preparation of 1H-imidazole-4-carbaldehyde (Formula-I) by Scheme-I:

Example 1:
Preparation of (1H-imidazol-4-yl)methanol:
To a stirred solution of basic copper carbonate (245 g) in water (800 mL) was added 25% aqueous ammonia solution (800 g) slowly at 25 to 35°C. Reaction mass was stirred at same temperature for 30 minutes. Added 37-40% formaldehyde (7.0 eq.) slowly at 25 to 35°C over a period of 30 minutes. Reaction mass was stirred at same temperature for 30 to 40 minutes. A solution of fructose (100 g) in water (100 mL) was added slowly at 10 to 15°C. Reaction mass was further heated to 95 to 100°C for 4 hours. Cooled the reaction mass to 0-5°C and washed the resulting precipitate after filtration with pre-cooled water (3 vol). Resulting precipitate was suspended in water (500 mL) and treated with sodium dithionite (48 g) in 3 lots at 50°C. Reaction mass was further heated to 65 to 70°C for 1 hour. Filtered reaction mass on celite bed and washed with warm water (200mL). Filtrates were evaporated under vacuum below 60°C to obtain crude (1H-imidazol-4-yl)methanol (51.2 g).
Example 2:
Purification of crude (1H-imidazol-4-yl)methanol:
A solution of crude (1H-imidazol-4-yl)methanol (51.2 g) in Isopropyl alcohol (IPA) (500 mL) was heated to 80°C for 30 to 60 minutes. Cooled the reaction mixture to 60 to 70°C and filtered. Filtrates were collected and distilled under vacuum at below 45 to 50°C to obtain (1H-imidazol-4-yl)methanol (45 g; yield: 82.5%).
Example 3:
Conversion of (1H-imidazol-4-yl)methanol into 1H-imidazole-4-carbaldehyde:
To a stirred solution of (1H-imidazol-4-yl)methanol (45 g) in acetonitrile (900 mL) was added manganese dioxide (4.5 eq.) in lot wise at 40 to 50°C over a period of 20 minutes. Reaction mixture was further heated to 80 to 85°C for 10 to 12 hours for completion of reaction. Filtered the hot reaction mass on celite bed. Resulting filtrates were evaporated under vacuum at below 45 to 50°C to obtain crude 1H-imidazole-4-carbaldehyde (39.8 g).
Example 4:
Conversion of (1H-imidazol-4-yl)methanol into 1H-imidazole-4-carbaldehyde:
To a stirred solution of (1H-imidazol-4-yl)methanol (40 g) in methanol (200 mL) acetonitrile (600 mL) was added manganese dioxide (4.5 eq.) in lot wise at 40 to 50°C over a period of 20 minutes. Reaction mixture was further heated to 80 to 85°C for 10 to 12 hours for completion of reaction. Filtered the hot reaction mass on celite bed. Resulting filtrates were evaporated under vacuum at below 45 to 50°C to obtain crude 1H-imidazole-4-carbaldehyde (36.6 g).
Example 5:
Purification of 1H-imidazole-4-carbaldehyde:
A solution of crude 1H-imidazole-4-carbaldehyde (39.8 g) in Isopropyl alcohol (IPA) (8.0 vol) was heated to 75 to 80°C for 10 to 15 minutes. Added activated charcoal (1.12gm) at same temperature and stirred for additional 30 minutes. Filtered the hot reaction mixture on celite bed and resulting filtrates were evaporated under reduced pressure at below 45 to 50°C. Resulting residue was further dissolved in Isopropyl alcohol (IPA) (60 mL). Cooled the reaction mixture to 0-5°C and stirred for 30 to 60 minutes. Resulting precipitate was filtered and dried at 55 to 60°C to obtain 1H-imidazole-4-carbaldehyde (38.5 g, yield: 87.5%) as a pale yellow solid.
1HNMR (400MHz, DMSO-d6): δ 12.906 (1 H), 9.763 (1 H), 8.048 (2 H).

Dated this Oct, 09th 2024

Signature:
VINOD SAGAR TIRUMALARAJU
Patent Agent Reg. No.: IN/PA-5328

We claim:

1. An improved process for preparation of 1H-imidazole-4-carbaldehyde of Formula-I, which comprising,
a) reaction of fructose with basic cupric carbonate, ammonia and formaldehyde in presence of a protic solvent to obtain copper complex of corresponding imidazole derivative,
b) cleavage of copper-imidazole complex by adding sodium dithionite to obtain crude (1H-imidazol-4-yl)methanol,
c) optionally, purification of crude (1H-imidazol-4-yl)methanol obtained in step b) with an alcoholic solvent to obtain (1H-imidazol-4-yl)methanol,
d) adding manganese dioxide (MnO2) to a solvent containing (1H-imidazol-4-yl)methanol obtained in step c) to obtain crude 1H-imidazole-4-carbaldehyde,
e) purification of crude 1H-imidazole-4-carbaldehyde obtained in step d) with an alcoholic solvent to obtain 1H-imidazole-4-carbaldehyde.
2. The process as claimed in claim 1, wherein the protic solvent used in step a) is water.
3. The process as claimed in claim 1, wherein the solvent used in oxidation step d) is selected from toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, ethyl acetate, isopropyl acetate, acetone, acetonitrile, C1 to C8 alcoholic solvent and like or a mixture thereof.
4. The process as claimed in claim 3, wherein the C1 to C8 alcoholic solvent used in step d) is Methanol.
5. The process as claimed in claim 1, wherein the alcoholic solvent used in step c) and e) is selected from C1 to C8 alcoholic solvent and like or mixtures thereof.
6. The process as claimed in claim 5, wherein the C1 to C8 alcoholic solvent used in step c) and e) is Isopropyl alcohol (IPA).

Dated this Oct, 09th 2024

Signature:
VINOD SAGAR TIRUMALARAJU
Patent Agent Reg. No.: IN/PA-5328

TITLED: AN IMPROVED PROCESS FOR PREPARATION OF “1H-IMIDAZOLE-4-CARBALDEHYDE” AND ITS PURIFICATION THEREOF


ABSTRACT
The present invention relates to an improved process for preparation of 1H-imidazole-4-carbaldehyde of Formula-I. The invention further relates to purification of 1H-imidazole-4-carbaldehyde of Formula-I.

(Formula I)

Dated this Oct, 09th 2024

Signature:
VINOD SAGAR TIRUMALARAJU
Patent Agent Reg. No.: IN/PA-5328

, Claims:We claim:

1. An improved process for preparation of 1H-imidazole-4-carbaldehyde of Formula-I, which comprising,
a) reaction of fructose with basic cupric carbonate, ammonia and formaldehyde in presence of a protic solvent to obtain copper complex of corresponding imidazole derivative,
b) cleavage of copper-imidazole complex by adding sodium dithionite to obtain crude (1H-imidazol-4-yl)methanol,
c) optionally, purification of crude (1H-imidazol-4-yl)methanol obtained in step b) with an alcoholic solvent to obtain (1H-imidazol-4-yl)methanol,
d) adding manganese dioxide (MnO2) to a solvent containing (1H-imidazol-4-yl)methanol obtained in step c) to obtain crude 1H-imidazole-4-carbaldehyde,
e) purification of crude 1H-imidazole-4-carbaldehyde obtained in step d) with an alcoholic solvent to obtain 1H-imidazole-4-carbaldehyde.
2. The process as claimed in claim 1, wherein the protic solvent used in step a) is water.
3. The process as claimed in claim 1, wherein the solvent used in oxidation step d) is selected from toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, ethyl acetate, isopropyl acetate, acetone, acetonitrile, C1 to C8 alcoholic solvent and like or a mixture thereof.
4. The process as claimed in claim 3, wherein the C1 to C8 alcoholic solvent used in step d) is Methanol.
5. The process as claimed in claim 1, wherein the alcoholic solvent used in step c) and e) is selected from C1 to C8 alcoholic solvent and like or mixtures thereof.
6. The process as claimed in claim 5, wherein the C1 to C8 alcoholic solvent used in step c) and e) is Isopropyl alcohol (IPA).