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Synthetic method of diphosphonate medicine

A bisphosphonate and synthesis method technology, which is applied in the synthesis process and production application field of bisphosphonate drugs, can solve the problems of severe heat release, less supply, and difficulty in the treatment of three wastes, so as to improve economic benefits and reduce The effect of pressure

Inactive Publication Date: 2014-10-01
陕西汉江药业集团股份有限公司
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AI Technical Summary

Problems solved by technology

Each method has its own characteristics, but in terms of industrial production, there are also shortcomings, such as: raw materials are not environmentally friendly, which brings difficulties to the treatment of three wastes, or the price of raw materials is high and the supply is small, and the process does not have industrial value; The requirements for equipment performance are high, and ordinary equipment cannot meet the needs; the process reaction and processing operation are complex, the production cycle is long, and the industrial production capacity is low; the chemical reaction is not properly controlled, the heat release is violent, and the safety of industrial production is difficult to guarantee

Method used

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preparation example Construction

[0033] 1) Preparation of crude bisphosphonates

[0034] 1.1] Add methanesulfonic acid, aminoalkanoic acid, phosphonylation reagent (phosphonite, phosphonyl chloride, etc.) -Alanine and other aminoalkanoic acids with substituent groups on the amino group; phosphonylating reagents include but not limited to phosphonyl chloride, sulfurous acid and their esters; methanesulfonic acid can also be used by other sulfonic acid liquid solvents Replaced; the material dissolution temperature range is 30-130°C; the molar ratio of the material is: aminoalkanoic acid: methylsulfonic acid: phosphonylation reagent: phosphorus trichloride / phosphorus pentachloride = 1.0: 3.0 ~ 10.0: 0.6 ~2.0: 1.0~5.0.

[0035] 1.2] Add phosphorus trichloride or phosphorus pentachloride dropwise, the temperature is in the range of 40-80°C, the reaction is mild, and the reaction is kept for 5-25 hours.

[0036] 1.3] After the reaction is completed, add water dropwise. The temperature range for adding water is 0-...

Embodiment 1

[0044] Synthesis of Alendronate Sodium

[0045] 1] Synthesis of crude product of alendronate sodium

[0046] 1.1] Put 750.0g of methanesulfonic acid, 200.0g of 4-aminobutyric acid and 240.0g of phosphorous acid into a 10L reaction bottle; heat up to 40-80°C, add 850.0g of phosphorus trichloride dropwise. 80 ℃ heat preservation reaction for 10 to 20 hours;

[0047] 1.2] Cool down to 5-35°C, add 3000.0g of water, then raise the temperature to 70-100°C, keep warm for 4-10 hours; slowly add about 3000.0g of 50% liquid caustic soda dropwise, adjust the pH to 3.8-4.5, and cool down to 3 ~20°C; filter with suction, wash the filter cake twice with 500.0 g of water, and drain to obtain 813.0 g of crude alendronate sodium.

[0048] 2] Refining of alendronate sodium

[0049] 2.1] Put the crude alendronate sodium obtained in the above step 1.2] into a 3L reaction bottle, 2400.0g of water, heat up to 40-80°C, add 80.0g of activated carbon, continue to heat up to 60-120°C, and keep warm ...

Embodiment 2

[0053] Synthesis of Pamidronate Disodium

[0054] 1) Synthesis of Pamidronate Disodium Crude Product

[0055] 1.1] Put 648.0g of methanesulfonic acid, 200.0g of 3-aminobutyric acid and 207.0g of phosphorous acid into a 10L reaction bottle; raise the temperature to 40-80°C, add 734.0g of phosphorus trichloride dropwise, after the dropwise addition, 40 ~80℃ heat preservation reaction for 10~20 hours;

[0056] 1.2] Cool down to 5-35°C, add 2600.0g of water, then raise the temperature to 70-100°C, keep warm for 4-10 hours; slowly add about 2600.0g of 50% liquid caustic soda dropwise, adjust the pH to 4.4-4.9, and cool down to 3 ~20°C; filter with suction, wash the filter cake twice with 432.0 g of water, and drain to obtain 835.0 g of crude pamidronate disodium.

[0057] 2] Refining of Pamidronate Disodium

[0058] 2.1] Put the crude pamidronate disodium obtained in the above step 1.2] into a 3L reaction bottle, 2500.0g of water, heat up to 40-80°C, add 84.0g of activated carbo...

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Abstract

The invention relates to a synthetic method of a diphosphonate medicine. The synthetic method comprises the following steps: 1.1) adding a sulfoacid liquid solvent, amino alkyl acid and a phosphorylation agent; stirring and heating, wherein the temperature range is 30-130 DEG C; fully dissolving; 1.2) dropping phosphorus trichloride or phosphorus pentachloride and preserving heat at 40-80 DEG C to react; 1.3) dropping water, then heating to warm, preserving heat at 70-100 DEG C and completing a hydrolysis reaction to obtain a solution in a diphosphonic acid structure; 1.4) kalifying to neutralize, cooling and devitrifying, and centrifugally washing to obtain a coarse product of diphosphonate; 2.1) returning the obtained coarse product of diphosphonate to a tank and adding a solvent, stirring and heating, and dissolving; 2.2) after fully dissolving, decoloring and press-filtering; and 2.3) cooling and devitrifying the solution, and centrifugally washing and drying the obtained diphosphonate crystals. The chemical synthetic method of the diphosphonate medicine provided by the invention solves the potential safety hazards such as a plenty of heat release and explosion and boiling in reaction on the premise of guaranteeing the yield.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and specifically relates to a synthesis process method and production application of bisphosphonate drugs. Background technique [0002] Bisphosphonate compounds are an important drug for the treatment of osteoporosis, administered orally or intravenously, for the treatment of osteoporosis, deforming osteoinflammation, hypercalcemia caused by malignant tumor bone metastasis and osteoporosis. Pain etc. [0003] Bisphosphonates are strong inhibitors of osteoclastosis, where T 1 / 2 : Up to 12 years, the effect is very long-lasting. Bisphosphonate compounds can be firmly adsorbed on the surface of hydroxyapatite, the main component of bone, inhibiting its formation and dissolution, as well as inhibiting soft tissue calcification and bone resorption. So far, "three generations of products" have been developed. Bisphosphonates are developing rapidly. They have significant curative effects on inhibiti...

Claims

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Application Information

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IPC IPC(8): C07F9/38
Inventor 张佳燕国武唐耀光陈峙路俊宏
Owner 陕西汉江药业集团股份有限公司
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