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Method for synthesizing 4-(1-hydroxyl-1-methylethyl)-2-propyl iminazole-5-carboxylic ethyl ester

A technology of propylimidazole and methyl ethyl, which is applied in the field of chemical synthesis, can solve problems such as difficult precipitation of solids, influence on yield, crystal color, and poor decolorization effect by adding activated carbon, and achieve the effect of simple process and low cost

Active Publication Date: 2011-05-18
NANTONG SHIMEIKANG PHARMA CHEM
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  • Abstract
  • Description
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Problems solved by technology

However, in the actual synthesis process of this method, it is found that the product obtained by spinning out acetonitrile after the first step of the reaction is difficult to precipitate solids, and the cyclization reaction is prone to produce more polar black viscous substances, and the decolorization effect of adding activated carbon after cyclization is very poor. , which greatly affects the yield and the precipitation of crystals and the color of crystals
There are also materials using n-butyric acid and o-phenylenediamine as raw materials to condense into 2-propylbenzimidazole under microwave irradiation, then oxidize and open the ring to obtain 2-propylimidazole dicarboxylic acid, and then undergo esterification and Gringard reaction 2-Propyl-4-[(1-hydroxyl-1-methyl)ethyl]-1H-imidazole-5-carboxylic acid ethyl ester was obtained with a total yield of 32.2%, which was very low and unfavorable for industrial production

Method used

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  • Method for synthesizing 4-(1-hydroxyl-1-methylethyl)-2-propyl iminazole-5-carboxylic ethyl ester
  • Method for synthesizing 4-(1-hydroxyl-1-methylethyl)-2-propyl iminazole-5-carboxylic ethyl ester
  • Method for synthesizing 4-(1-hydroxyl-1-methylethyl)-2-propyl iminazole-5-carboxylic ethyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Synthesis of 2-propylimidazole-4,5-dicarbonitrile (III).

[0034] In a 1500ml three-necked flask, add 200.0g (1.85mol) of diaminomaleonitrile and 300.0g (2.02mol) of trimethyl orthobutyrate and be dissolved in 500ml of anhydrous methanol, stir and reflux for 8 hours, and TLC detects that the reaction ends. Activated carbon (5g) was added to the system, the reaction was continued for 1 hour, filtered while it was hot, the filter cake was washed with 20ml of methanol, and ammonia gas (200g in total) was slowly introduced into the obtained filtrate in 3 batches under an ice bath, and the temperature of the system was maintained at 0-15°C. About 8 hours, TLC detects that the reaction is complete, 2 / 3 of methanol is recovered under reduced pressure, the residue is left standing to obtain block crystals, the crystals are filtered out, washed with cold methanol (50ml), and air-dried to obtain a white solid product with a yield of 99%. Content 99.8%, mp: 141~142.5℃, ...

Embodiment 2

[0037] Example 2: Synthesis of 2-propylimidazole-4,5-dicarbonitrile (III).

[0038] In a 1500ml three-necked flask, add 200.0g (1.85mol) of diaminomaleonitrile and 280.0g (1.90mol) of trimethyl orthobutyrate and be dissolved in 500ml of dehydrated alcohol, stir and reflux for 8 hours, TLC detection reaction ends, to this Activated carbon (5g) was added to the system, the reaction was continued for 1 hour, filtered while it was hot, the filter cake was washed with 20ml of ethanol, and ammonia gas (200g in total) was slowly introduced into the filtrate in 3 batches under an ice bath to maintain the temperature of the system at 0-15°C. About 8 hours, TLC detected that the reaction was complete, 2 / 3 of the methanol was recovered under reduced pressure, and the residue was allowed to stand still to obtain massive crystals, which were filtered off, washed with cold methanol (50ml), and air-dried to obtain a white solid product with a yield of 100%.

Embodiment 3

[0039] Example 3: Synthesis of diethyl 2-propylimidazole-4,5-dicarboxylate (IV).

[0040] Add 50.0 g (0.3 mol) of 2-propylimidazole-4,5-dinitrile (III) into a 1500 ml three-neck flask, slowly add 500 g of 20% (w / w) ethanol solution of hydrogen chloride dropwise, and reflux for 6 days , TLC showed that the reaction was complete, evaporated to dryness under reduced pressure, added saturated sodium bicarbonate solution (300ml) and ethyl acetate (100ml) to the residue and stirred at room temperature for 5 minutes, separated into layers, and the aqueous layer was washed with ethyl acetate (100ml×3) Extracted, combined organic layers, dried over anhydrous magnesium sulfate, filtered, and recovered ethyl acetate under reduced pressure to obtain white solid product 2-propylimidazole-4,5-dicarboxylated diethyl ester (IV), with a yield of 90%. The content is 99.7%. mp: 82~83.5℃, the detection parameters are as follows:

[0041] 1 H NMR (300MHz, CDCl 3 +D 2 O) δppm: 0.83 ~ 0.91 (3H,...

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Abstract

The invention discloses a method for synthesizing 4-(1-hydroxyl-1-methylethyl)-2-propyl iminazole-5-carboxylic ethyl ester, which comprises the steps of: using trimethyl orthobutyrate and diaminomaleonitrile as raw materials, and performing backflow reaction to prepare an imidic acid ester intermediate in presence of alcohols solvents; adding active carbon, continuously performing backflow for 1 hour, and filtering while the mixture is hot; cooling the filtrate to 0-15 DEG C, and introducing ammonia to prepare 2-propyl iminazole-4,5-dinitrile; adding the 2-propyl iminazole-4,5-dinitrile to a mixed solution of hydrochloric acid and ethanol and esterfying in backflow state to prepare 2-propyl iminazole-4,5-diethyl dicarboxylate; and performing reaction of 2-propyl iminazole-4,5-diethyl dicarboxylate and a Grignard reagent to prepare the 4-(1-hydroxyl-1-methylethyl)-2-propyl iminazole-5-carboxylic ethyl ester. By adopting the synthesizing method, the total yield of the synthesized 4-(1-hydroxyl-1-methylethyl)-2-propyl iminazole-5-carboxylic ethyl ester is 81% which is obviously superior to the total yield (55%) of the traditional references; and the invention has the advantages of concise process and low cost and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a synthesis method of ethyl 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylate. Background technique [0002] The 2-substituted 4,5-dinitrile imidazole series compound is an important intermediate, not only an important intermediate used in olmesartan, but also widely used in pesticides, medicines, and other chemicals, so , it is very necessary to further deepen its synthesis process research. Its structure is as follows: [0003] [0004] In recent years, although some researchers have continuously synthesized a series of 2-substituted compounds of this type, basically using diaminomaleonitrile as a raw material, and the methods have been continuously improved. In the literature on the synthesis of olmesartan medoxomil, diaminomaleonitrile and trimethyl orthobutyrate are used as starting materials to reflux in acetonitrile to generate imidat...

Claims

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Application Information

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IPC IPC(8): C07D233/90
Inventor 王秀云朱宣华刘一超王俊华
Owner NANTONG SHIMEIKANG PHARMA CHEM
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