Improved telmisartan preparation process

A process improvement, telmisartan technology, applied in the direction of organic chemistry, can solve the problems of unfavorable industrial production, large environmental pollution, cumbersome operation, etc., and achieve the effect of saving production cost, less environmental pollution, and simplified operation

Inactive Publication Date: 2013-09-25
BEIJING INSTITUTE OF TECHNOLOGYGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The purpose of the present invention is to solve the difficult problems that are unfavorable for industrial production such as high cost, high environmental pollution and cumbersome operation in the exist

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Preparation of methyl 3-methyl-4-nitrobenzoate (2)

[0019] Add 300g of 3-methyl-4-nitrobenzoic acid 1 (1.66mol) and 1000mL of methanol into a dry 3L three-necked flask equipped with a reflux condenser and a thermometer, and make a simple tail gas absorption device on the reflux condenser. For NaOH aqueous solution. Under electromagnetic stirring, 100 g of thionyl chloride (0.85 mol) was added dropwise with a constant pressure dropping funnel, and the temperature of the reaction solution was controlled between 30-40 ° C during the dropping process, and the reaction solution was a milky white solution at this time. The dropwise addition was completed in about 45 minutes, and the temperature was raised to 60°C. At this time, the reactant was a clear yellow solution. Stir and reflux at this temperature for 2 hours, stop heating, and cool the reaction solution slowly, and a large amount of solids precipitate out at 50°C. Continue to cool down to 30°C, add 1000mL of water ...

Embodiment 2

[0021] Preparation of 3-methyl-4-aminobenzoic acid methyl ester (3)

[0022] In a 2L hydrogenation kettle, add 1.2mL of absolute ethanol, 6.5g of Raney Ni catalyst and 130g of compound 2, pump out the air with an oil pump, and pass N 2 The air in the kettle was exhausted three times, and H was introduced into the kettle. 2 Gas to 1.2MPa. Adjust the reactor controller, raise the temperature to 80°C and observe the pressure inside the reactor. When the hydrogen pressure no longer decreases, react under this condition for 2 hours. The reactant was cooled to room temperature, the residual hydrogen in the kettle was discharged, and the reaction solution was emitted. The catalyst was removed by filtration, and the ethanol solvent was evaporated under reduced pressure to obtain 105.5 g of a white solid with a yield of 96.2%.

Embodiment 3

[0024] Preparation of methyl 3-methyl-4-n-butyramide benzoate (4)

[0025] Add 182 g (1.1 mol) of compound 3 into a 3 L three-neck flask equipped with a reflux condenser and a thermometer, and add 1.6 L of acetonitrile and 350 mL of triethylamine in sequence under stirring. Under the condition of ice-water bath, 160.5 g of n-butyryl chloride (1.5 mol) was added dropwise to the three-necked flask through a constant pressure dropping funnel, and the temperature during the dropping process was controlled not to exceed 20°C. At this time, the reaction liquid was a milky white liquid. After the dropwise addition, the temperature was slowly raised to reflux, and the solution was clear and transparent. The reaction was stirred for 2 h, cooled naturally to room temperature, and the precipitated white solid was filtered off. The acetonitrile solution was evaporated under reduced pressure, and the solid residue was washed with saturated Na 2 CO 3 The solution and water were washed se...

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Abstract

The invention provides an improved process for preparing a telmisartan raw material medicament. The improved process comprises the following step: preparing an intermediate 2-n-propyl-4-methyl-benzimidazole-6-carboxylic acid by using methyl 4-butylacetamino-3-methylbenzoate as a raw material through four steps, namely nitration, reduction, cyclization and hydrolysis. According to the process, crude products in nitrification, reduction and cyclization reactions are not subjected to purification and separation, and a target product can be separated by regulating the pH of a reaction liquid obtained in a hydrolysis reaction to be between 6 and 7, so that the problems of complicated operation and yield loss caused by separation of nitrified and reduced products by recrystallization and chromatographic separation of a cyclized product by a column are solved. Therefore, the purity of the prepared telmisartan crude product is over 99 percent after recrystallization. The improved process is simple to operate, high in yield and low in cost, and is advantageous to industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemistry, in particular to simplify the production operation of 2-n-propyl-4-methyl-benzimidazole-6-carboxylic acid so as to reduce the production cost of telmisartan. Background technique [0002] 2-n-propyl-4-methyl-benzimidazole-6-carboxylic acid is a key intermediate for the preparation of antihypertensive drug telmisartan. Telmisartan can completely block the renin-angiotensin system because of its specific inhibitory effect on ATⅡ. In addition, telmisartan is the ATⅡ receptor antagonist drug with the longest half-life, so it has become one of the drugs commonly used clinically for the treatment of hypertension. [0003] [0004] For the synthesis technique of 2-n-propyl-4-methyl-benzimidazole-6-carboxylic acid, there are many related patents and literature reports both at home and abroad (such as CN101838243A, CN101921235A, CN1412183A, US5591762, CN102267949A, WO200510837, J. Med.chem.1993, 36(2...

Claims

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Application Information

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IPC IPC(8): C07D235/08C07D235/18
Inventor 周智明苏晓军章军
Owner BEIJING INSTITUTE OF TECHNOLOGYGY
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