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Process for the preparation of biphosphonic acids and salts thereof

A technology for bisphosphonic acid compounds and carboxylic acids, which is applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc. Yield-enhancing effect

Inactive Publication Date: 2009-12-16
霍维奥恩联合有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Sulfolane is a class II solvent, and while the patent mentions that the reaction mixture is a homogeneous mixture, the process was found to be difficult to reproduce on an industrial scale due to the necessity to distill phosphorous acid under reduced pressure

Method used

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  • Process for the preparation of biphosphonic acids and salts thereof
  • Process for the preparation of biphosphonic acids and salts thereof
  • Process for the preparation of biphosphonic acids and salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Preparation of risedronate sodium salt:

[0059] 3-pyridineacetic acid (7.5g; 0.0432mol) and H 3 PO 3 (5.31 g; 0.0648 mol) in N,N'-dimethylethylene urea (DMEU) (30 ml) was heated to a temperature of 40°C to 50°C. PCl 3 (7.5ml; 0.0852mol) was slowly added to the resulting suspension. The resulting mixture was heated to a temperature of 50°C to 60°C and stirred until the reaction was complete. Reaction completion was monitored by HPLC. Water was slowly added to the reaction mixture, and the resulting solution was heated with stirring at a temperature of 80°C to 100°C until the reaction was complete. The reaction mixture was cooled to room temperature and the pH was adjusted to about pH 8-9 with aqueous sodium hydroxide. The resulting solution was filtered and the pH of the solution was adjusted to 4.5 to 5.0. Ethanol was added and a solid precipitated. The solid was filtered, washed, and dried under vacuum at a temperature of 45°C to 55°C to constant weight. 8.9 ...

Embodiment 2

[0065] Preparation of risedronic acid free acid:

[0066] 3-pyridineacetic acid (25g; 0.142mol) and H 3 PO 3 (17.7 g; 0.216 mol) in N,N'-dimethylethylene urea (DMEU) (100 ml) was heated to a temperature of 40°C to 50°C. PCl 3 (25.2ml; 0.284mol) was slowly added to the resulting suspension. The resulting mixture was heated to a temperature of 50°C to 60°C and stirred until the reaction was complete. Reaction completion was monitored by HPLC. Water was slowly added to the reaction mixture, and the resulting solution was heated with stirring at a temperature of 80°C to 100°C until the reaction was complete. The reaction mixture was cooled to room temperature and the pH was adjusted to about pH 8-9 with aqueous sodium hydroxide. The resulting solution was filtered, the pH of the solution was adjusted to 1.5 to 2.0, ethanol was added, and a solid precipitated. The solid was filtered, washed, and dried under vacuum at a temperature of 45°C to 55°C to constant weight.

[0067...

Embodiment 3

[0070] Preparation of risedronic acid free acid crude product:

[0071] 3-pyridineacetic acid (7.5g; 0.0432mol)) and H 3 PO 3 (5.31 g; 0.0648 mol) in N,N'-dimethylethylene urea (DMEU) (30 ml) was heated to a temperature between 40°C and 50°C. PCl 3 (7.5ml; 0.0852mol) was slowly added to the resulting suspension. The resulting mixture was heated to a temperature of 50°C to 60°C and stirred until the reaction was complete (by HPLC). Water is slowly added to the reaction mixture, and the resulting solution is heated to a temperature of 80°C to 100°C with stirring until the reaction is complete. The reaction mixture was cooled to room temperature. The solid was filtered, washed, and dried under vacuum at a temperature of 45°C to 55°C to constant weight. 12.9 g of crude risedronic acid were obtained.

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Abstract

A process for the preparation of biphosphonic acids and pharmaceutical acceptable salts thereof, comprises reacting a carboxylic acid with phosphorous trichloride and phosphorous acid in the presence of an aprotic polar solvent.

Description

technical field [0001] The present invention relates to the preparation method of bisphosphonic acid and its salt. Background technique [0002] Bisphosphonate compounds, known as bisphosphonates, are a class of pharmaceutically active substances used in the treatment of bone diseases and calcium metabolism disorders. Such diseases include, but are not limited to, osteoporosis, Paget's disease, and osteolytic metastasis. [0003] Bisphosphonates are analogs of an endogenous substance called pyrophosphate, which is a natural inhibitor of bone resorption. Pyrophosphate is characterized by its P-O-P bond. However, pyrophosphate cannot be used as a therapeutic agent because of its short biological half-life due to rapid enzymatic cleavage of its P-O-P bond. Accordingly, there is a need for synthetic analogs of pyrophosphoric acid that are less susceptible to hydrolysis. Bisphosphonic acids are synthetic analogs of pyrophosphoric acid in which the central oxygen atom is repla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/38C07F9/58C07F9/6506
CPCC07F9/582C07F9/3873C07F9/386C07F9/65061C07F9/58C07F9/6506
Inventor J·巴普蒂斯塔Z·门德斯
Owner 霍维奥恩联合有限公司
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