Preparation method of olmesartan intermediate

A technology of olmesartan medoxomil and intermediates, applied in the field of drug synthesis, can solve the problems of difficult industrial production, difficult removal of solvents, poor product quality, etc., and achieve the effects of easy control of process conditions, good product quality and low production cost

Inactive Publication Date: 2015-05-06
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] 4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] Methyl] imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester has the following preparation methods: Chinese Patent Publication No. CN1532195A, CN1045770C and CN1381453A etc. provide the medicine olmesartan that can be prepared for the treatment of hypertension, and Japanese open patent JP [31] 27098, European patent EP503785, Journal of Medicinal chemistry1996, Vo1.39, all report on No.1323-338 The preparation method of olmesartan is disclosed. The method is formed by linking the imidazole part and the biphenyl part. During the reaction, side reactions easily occur to form by-products, which bring difficulties to subsequent processing and make it difficult to separate and remove the by-products. The obtained product The quality is poor, and the yield is also low, it is difficult to realize industrial production
Due to the particularity of the properties of this compound, using the conventional recrystallization purification method, it is necessary to use a large amount of solvent to dissolve in the boiling state when dissolving, and the crystals are difficult to precipitate at low temperature or the crystals are less, resulting in a relatively low purification rate. Low
And it is difficult to remove the solvent under conventional vacuum heating and drying conditions, resulting in excessive solvent residue or deterioration of the compound

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0033](1) Add 160kg of N,N-dimethylacetamide in a 500L glass-lined reactor equipped with devices such as stirrer, thermometer, vacuum pressure gauge, etc., add 40kg of compound (Ⅲ) and 4.0kg of potassium hydroxide powder under stirring, Close the feeding port, replace the air with nitrogen and keep the pressure ≥ 0.01MPa, control the temperature of the reaction mixture under stirring, keep stirring at 35°C for 5 hours, then add 12kg of anhydrous potassium carbonate powder and 6.0kg of potassium iodide to the reaction kettle, The internal temperature of the reaction mixture was lowered to 0-5°C, and 16 kg of 4-chloromethyl-5-methyl-1,3-dioxol-2-one was added. After replacing the air with nitrogen, in the presence of nitrogen under positive pressure, raise the internal temperature of the reaction solution to 30-35°C within 1 hour. Transfer to a 2000L extraction kettle, add 480kg of ethyl acetate, wash with 1000kg of 10% sodium chloride aqueous solution three times, control the t...

Embodiment 2

[0037] (1) Add 280kg of N,N-dimethylacetamide to a 500L glass-lined reactor equipped with a stirrer, thermometer, vacuum pressure gauge, etc., add 40kg of compound (Ⅲ) and 12kg of potassium hydroxide powder under stirring, and close the At the feeding port, replace the air with nitrogen and keep the pressure ≥ 0.01MPa, control the temperature of the reaction mixture under stirring, keep stirring at 15°C for 3 hours, then add 4kg of anhydrous potassium carbonate powder and 2kg of potassium iodide to the reaction kettle, and then react The internal temperature of the mixed solution was lowered to 0-5°C, and 10 kg of 4-chloromethyl-5-methyl-1,3-dioxol-2-one was added. After replacing the air with nitrogen, in the presence of nitrogen under positive pressure, raise the internal temperature of the reaction solution to 45-50°C within 1 hour, and after holding the heat for 1 hour, reduce the internal temperature of the reaction mixture to 10°C, and the reaction solution Transfer to a...

Embodiment 3

[0041] (1) Add 200kg of N,N-dimethylacetamide in a 500L glass-lined reactor equipped with devices such as stirrer, thermometer, vacuum pressure gauge, etc., add 40kg of compound (Ⅲ) and 8.0kg of potassium hydroxide powder under stirring, Close the feeding port, replace the air with nitrogen and keep the pressure ≥ 0.01MPa, control the temperature of the reaction mixture under stirring and keep stirring at 20°C for 4 hours, then add 8.0kg of anhydrous potassium carbonate powder and 4.0kg of potassium iodide to the reaction kettle , the internal temperature of the reaction mixture was lowered to 0-5° C., and 12 kg of 4-chloromethyl-5-methyl-1,3-dioxol-2-one was added. After replacing the air with nitrogen, in the presence of nitrogen under positive pressure, raise the internal temperature of the reaction solution to 35-40°C within 1 hour. Transfer to a 2000L extraction kettle, add 600kg of ethyl acetate, wash with 1120kg of 10% sodium chloride aqueous solution three times, contr...

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Abstract

The invention belongs to the technical field of medicament synthesis, and in particular relates to a preparation method of an olmesartan intermediate. The preparation method comprises the following steps: enabling a compound (III) to react with a strong base in the presence of an organic solvent under the protection of nitrogen to generate a compound (II), enabling the compound (II) to react with 4-chloromethyl-5-methyl-1,3-dioxole-2-one under the catalysis of potassium carbonate and potassium iodide without separation, performing extraction with an organic solvent after reaction, and performing brine washing, concentration, crystallization, centrifuging and drying to obtain a crude product of a compound (I); and recrystallizing the crude product of the compound (I) by using the organic solvent, then centrifuging, and finally performing vacuum drying under the condition of alternate replacement of nitrogen and vacuum, thereby obtaining a high-quality product of the compound (I). The preparation method provided by the invention is stable in process and simple in operation, the process condition is easy to control, the after treatment is simple and convenient, less three wastes are generated, a mother solution can be continuously and circularly used, the product quality is good, the yield is high, the production cost is low, and a pilotscale experiment validates that the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of an olmesartan medoxomil intermediate. Background technique [0002] 4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] Methyl] imidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester has the following preparation methods: Chinese Patent Publication No. CN1532195A, CN1045770C and CN1381453A etc. provide the medicine olmesartan that can be prepared for the treatment of hypertension, and Japanese open patent JP [31] 27098, European patent EP503785, Journal of Medicinal chemistry1996, Vo1.39, all report on No.1323-338 The preparation method of olmesartan is disclosed. The method is formed by linking the imidazole part and the biphenyl part. During the reaction, side reactions easily occur to form by-products, which bring difficulties to subsequent processing and make it difficult to separate a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14
CPCC07D405/14C07D403/10
Inventor 朱连博
Owner SHANDONG XINHUA PHARMA CO LTD
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