Preparation method of olmesartan medoxomil

A technology of olmesartan medoxomil and benzyl olmesartan medoxomil is applied in the fields of pharmaceutical preparation and medicinal chemistry, and can solve problems such as unfavorable energy saving, emission reduction and environmental protection, complicated operation, increased production cost and sewage treatment cost, etc.

Inactive Publication Date: 2015-01-07
SHANGHAI SINE PROMOD PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Since the above two methods all need to remove the trityl protecting group, the target product can be obtained, and when using acetic acid to remove the protecting group, the amount of acetic acid is usually more than 10 times the equivalent of the reaction substrate, and it needs Neutralization with alkali will produce a large amount of waste liquid, and the operation is complicated, which reduces production efficiency, increases production costs and sewage treatment costs, and is not conducive to energy saving, emission reduction and environmental protection

Method used

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  • Preparation method of olmesartan medoxomil
  • Preparation method of olmesartan medoxomil
  • Preparation method of olmesartan medoxomil

Examples

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Embodiment 1

[0033] 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole- Preparation of ethyl 5-carboxylate

[0034]

[0035] Add 1-trityl-5-(4'-bromomethylbiphenyl-2-)-1H-tetrazole (500 g, 0.9 mol), 4-(1-hydroxy-1-methyl) to the autoclave ethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (180g, 0.75mol), potassium carbonate (390g), and then acetonitrile (7.5L) was added, and the reaction was heated under reflux for 3 to 5 hours. After monitoring the completion of the reaction by TLC, it was cooled to room temperature (25° C.), filtered, and the filtrate was concentrated to dryness at 40° C. under reduced pressure (-0.09 MPa). Methyl tert-butyl ether (1L) was added, stirred at room temperature (25°C) for crystallization for 2 hours, filtered and dried at 60°C under reduced pressure (-0.09MPa) to obtain a solid compound 4-(1-hydroxy-1-methylethyl) )-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate (440 g)...

Embodiment 2

[0037] 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole- Preparation of lithium 5‐carboxylate and trityl olmesartan medoxomil VII

[0038]

[0039] Add 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl to the kettle } Methylimidazole-5-carboxylate ethyl ester (358g, 0.5mol), lithium hydroxide (32g, 0.75mol), dioxane (8L) and water (4L), warm the reaction to 55°C, stir the reaction After 5 to 7 hours, after monitoring the completion of the reaction by TLC, the reaction system was cooled to 25° C., 2 L of ethyl acetate and 1 L of saturated brine were added to the reaction solution, and the layers were separated. The aqueous phase was extracted three times with ethyl acetate, each 2L, the organic phases were combined, and the organic phases were washed three times with saturated brine, then the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated at 40°...

Embodiment 3

[0041] 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid Preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (olmesartan medoxomil I)

[0042]

[0043] Trityl olmesartan medoxomil VII (800 mg, 1 mmol) in the reaction flask was dissolved in 4 mL of dichloromethane and 4 mL of methanol mixed solvent, 400 mg of acidic ion-exchange macroporous resin Amberlyst-15 was added, the reaction was stirred at room temperature, and the reaction was monitored by TLC After completion, filter, wash the resin with methanol, monitor the washings by TLC until no organics remain, combine the filtrates, and concentrate the filtrates to dryness at 40°C under reduced pressure (-0.09MPa) to obtain an oily substance, add dichloromethane (3mL) and heat to 40°C ℃ dissolved, filtered, the filtrate was concentrated to dryness at 40 ℃ under reduced pressure (-0.09MPa), ethyl acetate (3 mL) was added and heated to dissolve, cooled to 4 ℃ fo...

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Abstract

The invention provides a preparation method of olmesartan medoxomil, which comprises the following step: removing triphenylmethyl protecting group from triphenylmethyl olmesartan medoxomil VII in an organic solvent containing an acid ion exchange macroporous resin to obtain the olmesartan medoxomil I. The invention also provides a preparation method of the raw material triphenylmethyl olmesartan medoxomil VII compound. By using the acid ion exchange macroporous resin, the method has the advantages of mild reaction conditions, high reaction selectivity and fewer side reactions; the acid ion exchange macroporous resin can be filtered instead of neutralization or water washing after the reaction finishes, can be recycled, and has the advantages of high stability, high heat resistance, high mechanical strength and long service life; and thus, the method can overcome the defects in the prior art, lowers the reagent cost, is beneficial to environmental protection and suitable for industrial production, and has high application value.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to the preparation of medicines, in particular to a preparation method for preparing olmesartan medoxomil. Background technique [0002] Olmesartan Medoxomil (Olmesartan Medoxomil) is an oral and effective non-peptide angiotensin II receptor antagonist developed by Japan Sankyo Company. The drug was approved by the U.S. FDA in April 2004, and its trade name is Banicar. It is characterized by a long half-life. Taking it once a day can effectively control blood pressure within a day, so it is convenient to take. Compared with other angiotensin Ⅱ receptor antagonist drugs, olmesartan medoxomil has a small dose, fast onset, stronger and lasting antihypertensive effect, low incidence of adverse reactions, and has obvious advantages. Therefore, it is of great significance to develop olmesartan medoxomil, a highly effective, long-acting, and low-toxicity antihypertensive drug. [0003] Olmesartan m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14
CPCY02P20/55C07D405/14
Inventor 胡林森肖志勇李丁陈逵
Owner SHANGHAI SINE PROMOD PHARMA
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