144689-93-0Relevant articles and documents
Synthetic method for preparing olmesartan medoxomil intermediate through continuous flow
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Paragraph 0036-0044, (2021/09/04)
The invention discloses a synthetic method for preparing an olmesartan medoxomil intermediate through continuous flow, which belongs to the technical field of drug synthesis. The method comprises the following steps: step (1), dissolving a compound 2-propyl-4,5-imidazole dicarboxylic acid ethyl ester I in an organic solvent to form a reaction phase A; step (2), taking a commercially purchased methyl magnesium chloride solution as a reaction phase B; step (3), pumping the reaction phase A and the reaction phase B into a mixer by using a plunger pump at a certain flow rate, then feeding the mixture into a reactor, retaining for a certain time, quenching by using an acid water phase C, feeding the mixture into an oil-water continuous liquid separator, separating liquid to obtain an organic solution of a compound as shown in a formula II, desolventizing, and recrystallizing to obtain the compound as shown in the formula II. The technical problems of low purity and high cost in the existing preparation process are solved, the product is high in purity and few in impurities, the content of the key impurity A, the key impurity B and the key impurity C can be controlled to be 0.1% or below, the raw materials are cheap and easy to obtain, the reaction condition is mild, operation is easy and convenient, the synthesis efficiency is high, and the method is suitable for industrial production. A novel continuous flow path is provided for preparing the olmesartan medoxomil and the intermediate.
Synthesis method of olmesartan intermediate
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Paragraph 0033; 0040-0045, (2020/06/17)
The invention relates to the field of drug intermediate synthesis, in particular to a synthesis method of an olmesartan intermediate, which is characterized in that tartaric acid is used as a raw material, and the olmesartan intermediate is prepared by cyclization reaction, esterification reaction and methylation reaction. According to the synthesis method of the olmesartan intermediate, the totalyield can reach 60% or above, the yield is high, and economic benefits are high; the synthesis route is simple, basic raw materials are cheaper, side reactions are few, and purification is easy; andthe whole steps are easy to control, the method is more suitable for industrial application from raw materials to production, selection of ingredients and determination of the addition amount, and theproduction cost is low.
4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylic ethyl ester monohydrate
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Paragraph 0084; 0085; 0086; 0087, (2019/01/14)
The invention relates to a 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylic ethyl ester monohydrate (namely a compound shown in a formula 2) and a preparation method and application thereof. The compound can be obtained by crystallization in organic solvents, such as an acetone and water mixed solvent, in mutual solubility with water. The 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylic ethyl ester monohydrate is high in purity and yield, and subsequent olmesartan medoxomil synthesis is benefited.
A 4 - (1 - hydroxy -1 - methyl ethyl) -2 - propyl - 1H - imidazole -5 - carboxylic acid ethyl ester preparation method
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Paragraph 0048; 0049; 0052; 0053, (2017/08/25)
The invention relates to a preparation method of 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester and belongs to the technical field of medicament synthesis. In order to solve the problems of long reaction route, heavy pollution and low yield in the prior art, the invention provides a preparation method of 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester. The method comprises the following steps: in the presence of organic alkali, enabling a raw material alpha-chlorinated oxaloacetic acid diethyl ester to react with butanimidamide or acidic salt of butanimidamide to obtain an intermediate compound, then enabling the intermediate compound to perform Grignard reaction with CH3MgX to obtain 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester, wherein X in CH3MgX is halogen. The method disclosed by the invention has the advantages of short reaction route, less pollution, mild reaction condition and high yield.
Amazingel medoxomill intermediate 4 - (1-hydroxy-1-methyl ethyl) - 2-propyl-imidazol-5-carboxylic acid ethyl ester preparation method and application
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Paragraph 0070-0072, (2017/05/12)
The invention provides a preparation method of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazolyl-5-carboxylate (1). The method accurately controls the reaction material ratio, solvent composition, solvent consumption, reaction temperature, reaction time and other technological parameters, and obviously lowers the content of the impurity compound disclosed as Formula 3, thereby obtaining the high-purity olmesartan medoxomil. The invention also provides application of the compound disclosed as Formula 3 as a quality control standard substance in preparing the ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazolyl-5-carboxylate (1).
METHOD FOR PRODUCING 1-BIPHENYLMETHYLIMIDAZOLE COMPOUND
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, (2011/04/18)
The present invention provides a method for producing a 1-biphenylmethylimidazole compound having superior angiotensin II receptor antagonistic activity, or an intermediate thereof. The present invention provides a method for producing a compound having the formula (5) (R1 , Ra : H, an alkyl group) by oxidizing a compound having the formula (1) (R a : H, an alkyl group) using an oxidizing agent in the presence of a radical initiation reagent, and then reacting with an ammonia-generating reagent and a compound having the formula R 1 CHO (R 1 : H, an alkyl group) or a compound having the formula R1C(ORb)3 (R1: H,an alkyl group; Rb : an alkyl group).
PROCESS FOR THE PREPARATION OF 4-(1-HYDROXY-1-METHYLETHYL)-2-PROPYL-IMIDAZOLE-5-CARBOXYLATES
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, (2011/10/19)
The present invention discloses a process for obtaining 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (formula I) by the reaction of 4,4-dimethyl-2-propyl-4,6-dihydrofuro[3,4-d]imidazole (formula II), or its hydrolysis product, or its ring-opening product, with alcohol under appropriate catalytic conditions. Furthermore, the present invention also provides a process for obtaining high purity 4,4-dimethyl-2-propyl-4,6-dihydrofuro[3,4-d]imidazole (formula II), therefore purified compound of formula I can be produced. Producing of olmesartan medoxomil at high purity is assured by said processes. R in formula I is selected from C1-C6 alkyl.
An improved process for the preparation of olmesartan medoxomil
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Page/Page column 5, (2008/06/13)
Olmesartan medoxomil of high purity (99.3-99.7% by HPLC ) is prepared using an improved process of its intermediate, namely- ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate, comprising: Reacting ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate with N-(Triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2- yl]tetrazole in an organic solvent in presence of a base and a phase transfer catalyst in non-aqueous system to give after workup, ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate, which is further processed, by following improved reaction conditions in three steps to provide substantially pure [HPLC purity 99.3 to 99.7 %] olmesartan medoxomil. A further process relates to the purification of olmesartan medoxomil by treatment with isopropyl alcohol and methyl ethyl ketone.
ANGIOTENSIN II ANTAGONIST 1-BIPHENYLMETHYLIMIDAZOLE COMPOUNDS AND THEIR THERAPEUTIC USE
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, (2008/06/13)
Compounds of the following formula (I) or the formula (I) p : STR1 wherein R 1 is alkyl or alkenyl; R 2 and R 3 are hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, aryl, or aryl fused to cycloalkyl; R 4 is hydrogen, alkyl, alkanoyl, alkenoyl, arylcarbonyl, alkoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, tetrahydrofuryl, a group of formula--SiR a R b R c, in which R a, R b and R c are alkyl or aryl, alkoxymethyl, (alkoxyalkoxy)methyl, haloalkoxymethyl, aralkyl, aryl or alkanoyloxymethoxycarbonyl; R 5 is carboxy or--CONR 8 R 9, wherein R 8 and R 9 hydrogens or alkyl, or R 8 and R 9 together form alkylene; R 6 is hydrogen, alkyl, alkoxy or halogen; R. sup.7 is carboxy or tetrazol-5-yl; R p. sup.1 is hydrogen, alkyl, cycloalkyl or alkanoyl; R p 2 is a single bond, alkylene or alkylidene; R p 3 and R p 4 are each hydrogen or alkyl; R. sub.p 6 is carboxy or tetrazol-5-yl; and X p is oxygen or sulfur; and pharmaceutically acceptable salts and esters thereof. The compounds are AII receptor antagonists and thus have hypotensive activity and can be used for the treatment and prophylaxis of hypertension. The compounds may be prepared by reacting a biphenylmethyl compound with an imidazole compound.
Nonpeptide angiotensin II receptor antagonists: Synthesis, biological activities, and structure - Activity relationships of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds
Yanagisawa, Hiroaki,Amemiya, Yoshiya,Kanazaki, Takuro,Shimoji, Yasuo,Fujimoto, Koichi,Kitahara, Yoshiko,Sada, Toshio,Mizuno, Makoto,Ikeda, Masahiro,Miyamoto, Shuichi,Furukawa, Youji,Koike, Hiroyuki
, p. 323 - 338 (2007/10/03)
A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)-imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressor response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration. The most promising compounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (CS-866) and (pivaloyloxy)-methyl esters of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2′-1H-tetrazol-5-ylbiphenyl-4-yl) -methyl]imidazole-5-carboxylic acid (26c). A study involving stereochemical comparison of 26c with the acetylated C-terminal pentapeptide of AII was also undertaken.
