Preparation method for alendronic acid

A technology of acid new and acid aqueous solution, applied in the field of medicine and chemistry, can solve the problems of hidden danger, high cost of γ-aminobutyric acid, easy to be oxidized, etc., and achieve the effect of reducing production cost, good industrial application value and improving safety.

Active Publication Date: 2008-02-20
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the root cause of self-heating has not been solved, so there is also a safety hazard of self-heating out of control in the industrial production proc...

Method used

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  • Preparation method for alendronic acid

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Experimental program
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Effect test

Embodiment 1

[0027] 51g of 2-pyrrolidone and 100g of 70% sulfuric acid aqueous solution were hydrolyzed at a controlled temperature of 80°C for 20 hours. After the reaction was completed, 300ml of chlorobenzene was added, the temperature was stirred at 60°C, and 182g of phosphorus trichloride was added dropwise, and the addition was completed within 2 hours. After the addition, the temperature was controlled at 75°C to continue the reaction for 6 hours. After the reaction was over, 350ml of distilled water was added to the reaction system, the temperature was lowered to 20°C, and the organic layer was separated. After concentration under reduced pressure, it was added to 600ml of 40°C methanol for crystallization, cooled, filtered, and dried to obtain 93.1g of alendronic acid, with a yield of 62.3% and a content (HPLC) of 99.6%.

Embodiment 2

[0029] 51g of 2-pyrrolidone and 90g of 80% phosphoric acid aqueous solution were hydrolyzed at a controlled temperature of 100°C for 16 hours. After the reaction was completed, 200ml of fluorobenzene-difluorobenzene mixed solvent was added, stirring and temperature controlled at 63°C, and phosphorus trichloride was added dropwise. 175g, control the addition in 2.5 hours, after the addition, control the temperature at 80°C and continue the reaction for 5 hours. After the reaction is over, add 200ml of distilled water to the reaction system, lower the temperature to 25°C, separate the organic layer, and heat the water layer to reflux for 3 hours. Add 8 g of activated carbon for decolorization, filter, concentrate under reduced pressure, add to 310 ml of methanol at 45° C. to crystallize, cool, filter, and dry to obtain 73.6 g of alendronic acid, with a yield of 49.3% and a content (HPLC) of 99.5%.

Embodiment 3

[0031] 51g of 2-pyrrolidone and 150g of 95% methanesulfonic acid aqueous solution were hydrolyzed at a controlled temperature of 120°C for 30 hours. After the reaction was completed, 100ml of petroleum ether (bp: 60-90°C) was added after the reaction was completed, and the temperature was stirred at 56°C. Add 168g of phosphorus trichloride, and control the addition for 4.5 hours. After the addition, control the temperature at 60°C to continue the reaction for 8 hours. After the reaction is over, add 500ml of distilled water to the reaction system, cool it down to 10°C, separate the organic layer, and refill the water layer. Heat up and reflux for 1.5 hours, add 10 g of activated carbon for decolorization, filter, concentrate under reduced pressure, add to 400 ml of ethanol at 55°C to crystallize, cool, filter, and dry to obtain 79.5 g of alendronic acid, with a yield of 53.2% and a content (HPLC) of 99.2%.

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Abstract

The invention provides a novel preparation method of alendronic acid, pertaining to medicine and chemical technical field. The method solves the run-away safety hidden trouble caused by self-putting heat flush materials in the existing preparation method of alendronic acid. The novel preparation method of the alendronic acid comprises the steps: (1) 2-pyrrolidone is added in acidic aqueous solution, thus obtaining Gamma -aminobutyrate after reaction; (2) the Gamma -aminobutyrate system that is obtained from reaction is added into organic solvent of 2-pyrrolidone, and phosphorus tricholoride is added; (3) water is added in the reaction system to lower the temperature, remove organic horizon, and aqueous layer reflows, and active carbon is added to decolor, the solution is added in alcohol solution to be crystallized after filtration and concentration, thus obtaining alendronic acid through filtration and drying. The novel preparation method of the alendronic acid has the advantages of low cost, high yield rate, and good industrial application value.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a new preparation method of alendronic acid; it belongs to the field of medicine and chemistry. Background technique [0002] Alendronate sodium (alendronate sodium) is a third-generation bisphosphonate on the market for the treatment of osteoporosis, and is a new type of highly effective bone resorption inhibitor. Alendronic acid is an important intermediate for the synthesis of alendronate sodium. [0003] U.S. Patent (US4621077) preparation method of pharmaceutical active substance alendronic acid; U.S. patent (US4705651) preparation process of alendronic acid; U.S. patent (US4922007) preparation method of alendronic acid or its salt; Chinese patent (CN1660860) A method for preparing alendronic acid, all of which use gamma-aminobutyric acid, phosphorous acid, and phosphorus trichloride as main raw materials, but certain adjustments are made in the solve...

Claims

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Application Information

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IPC IPC(8): C07F9/38
Inventor 沈如恩孔佳郎陶激扬何琴飞
Owner ZHEJIANG LEPU PHARMA CO LTD
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