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4, 6-dihydrofuro [3, 4-d] imidazole-6- ketone derivative and salt and preparation method thereof

A technology of dihydrofuran and derivatives, applied in 4, can solve problems such as many by-products, difficulty in subsequent separation, and low yield

Inactive Publication Date: 2005-04-20
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Japanese Patent JP (31) 27098, European Patent EP503785, CN106563A, CN1381453A, Journal of Medical Chemistry, 1996, Vol.39, No: 1323-338 have reported the preparation method of olmesartan medoxomil, the method adopted When intermediates are used to prepare angiotensin II receptor antagonists (such as: olmesartan medoxomil), there are many by-products, harsh reaction conditions, subsequent separation difficulties, and low yields

Method used

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  • 4, 6-dihydrofuro [3, 4-d] imidazole-6- ketone derivative and salt and preparation method thereof
  • 4, 6-dihydrofuro [3, 4-d] imidazole-6- ketone derivative and salt and preparation method thereof
  • 4, 6-dihydrofuro [3, 4-d] imidazole-6- ketone derivative and salt and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0089] Preparation of 2-propylimidazole-4,5-dicarboxylate diethyl ester:

[0090] In a 2L four-neck round bottom flask equipped with a magnetic stirrer, a thermometer, a reflux condenser, and an oil bath heating, add 80 grams of 2-propylimidazole-4,5 dicarboxylic acid, 1000 ml of absolute ethanol, and a catalytic amount of concentrated sulfuric acid. The temperature was raised to reflux, and after 16 hours of reaction, the reaction solution was concentrated to 400ml. After cooling to room temperature, the reaction solution was transferred to a 3L beaker equipped with mechanical stirring and cooled by a water bath, 400ml of ethyl acetate and 600ml of water were added, and solid sodium bicarbonate was added in batches to adjust the solution to neutral. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate 200ml×3. The combined organic layers were washed once with water, dried over magnesium sulfate, filtered, and the solvent was evaporated to o...

Embodiment 2

[0094] 4-(1-Hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester

[0095] 2(a) Preparation of CH 3 MgI ether solution

[0096] In a 1L four-neck round bottom flask equipped with a mechanical stirrer, a thermometer, and a reflux condenser, 18.88 grams of magnesium powder and 100 ml of ether were added, and a solution of 49 ml of methyl iodide in 49 ml of ether was added dropwise at room temperature. After the addition, reflux for 15 minutes to obtain CH 3 MgI ether solution.

[0097] 2(b) Preparation of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate:

[0098] In a 2L four-necked round-bottomed flask equipped with a mechanical stirrer, a thermometer, and a reflux condenser, add 40 grams of 2-propylimidazole-4,5-diethyl ether, 800 ml of ether, and stir until dissolved. Add CH dropwise 3 MgI ether solution, and completed. The reaction mixture was further stirred at room temperature for 1 hour. Add 200 ml of ethyl acetate, dropwise add 35...

Embodiment 3

[0102] 4-(1-Hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid

[0103] In a 1L four-necked round bottom flask equipped with a magnetic stirrer, a thermometer, a reflux condenser, and an oil bath, add 73.35 grams of 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5 - Ethyl carboxylate, 150 ml acetone, 367 ml 10% sodium hydroxide solution. The temperature was raised to reflux, and the reaction was carried out for 2 hours. Cool to 0°C with an ice-water bath, add concentrated hydrochloric acid to adjust the solution to neutrality, stir for 30 minutes, filter with suction, wash, and dry to obtain 33.46 g of the title compound.

[0104] 1 H NMR (CDCl 3 , 400MHz): δ2.60 (2H, triplet), 1.65 (2H, sextet), 1.48 (6H, singlet), 0.86 (3H, triplet)

[0105] MS (Q-Tofmicro, ESI + ): 195.10, 213.12(M+1), 235.10(M+Na), 447.21(2M+Na)

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Abstract

The present invention relates to compounds of the general formula (A) shown below, pharmaceutically acceptable salts thereof and methods for preparing such compounds. ∴ R in formula (A) 1 , R 2 , R 3 , R 4 The definition of and the compound of formula (A) and its pharmaceutically acceptable salts and the preparation methods of such compounds are as described in the instructions. One of the purposes of the present invention is to provide a class of new 4,6-dihydrofuro [3,4-d] imidazol-6-one derivatives (general formula (A)) and salts thereof, the second is The synthesis of angiotensin II receptor antagonists (such as: olmesartan medoxomil) provides intermediates.

Description

technical field [0001] The present invention relates to a series of 4,6-dihydrofuro[3,4-d]imidazol-6-one derivatives and pharmaceutically acceptable salts thereof and preparation methods of such compounds. Background technique: [0002] 4,6-dihydrofuro[3,4-d]imidazol-6-one derivatives and pharmaceutically acceptable salts thereof are a class of novel compounds, which can be used as angiotensin II receptor antagonists (such as: Olmesartan medoxomil) is an important intermediate. Japanese Patent JP (31) 27098, European Patent EP503785, CN106563A, CN1381453A, Journal of Medical Chemistry, 1996, Vol.39, No: 1323-338 have reported the preparation method of olmesartan medoxomil, the method adopted When intermediates are used to prepare angiotensin II receptor antagonists (such as: olmesartan medoxomil), there are many by-products, harsh reaction conditions, subsequent separation difficulties, and low yields. Contents of the invention [0003] The technical problem to be solved...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/04
CPCC07D491/04
Inventor 张福利吴泰志
Owner SHANGHAI INST OF PHARMA IND CO LTD