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Preparation method of compound sodium ibandronate

A technology of sodium ibandronic acid and ibandronic acid, which is applied in the field of synthetic technology of sodium ibandronic acid, can solve the problems of large refining loss, difficult large-scale production of the process, and difficult stirring, so as to reduce the refining loss and refine The effect of frequency reduction

Inactive Publication Date: 2010-10-20
武汉同源药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] Through experiments, we found that the use of the above solvents has common disadvantages: the reaction product cannot be uniformly dispersed in the solvent, and the product is in the form of oily lumps, which adhere to the stirring rod, which not only affects the continuation of the reaction, but also makes stirring more and more difficult , if this situation is not resolved, it will make it difficult for the process to be used in mass production
The most difficult thing in the refining process of ibandronate sodium is to remove the chloride, because ibandronate sodium and sodium chloride are easily soluble in water, and ibandronate sodium is only soluble in water and insoluble in other solvents. The solvent must have water, and part of ibandronate sodium dissolves in water during refining, and the loss of refining is very large. It is often necessary to repeat refining 3-4 times, and the loss of each refining is about 10%.

Method used

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  • Preparation method of compound sodium ibandronate
  • Preparation method of compound sodium ibandronate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Raw material name Amount Mole number Mole ratio

[0033] 3-(N-Methyl-N-n-pentylamine) propionate hydrochloride 100 g 0.477 1

[0034] Phosphorus trichloride 79 grams 0.572 1.2

[0035] Phosphorous acid 121 grams 1.479 3.1

[0036] Acetonitrile 400g

[0037] Sodium hydroxide (50%) about 100mL

[0038] water 400mL

[0039] crafting process:

[0040] In a 1L three-neck flask equipped with a reflux device, 100 g of 3-(N-methyl-N-pentylamino) propionate hydrochloride, 121 g of phosphorous acid, and 400 g of acetonitrile were added. Stir, slowly raise the temperature to 70°C, add 79 grams of phosphorus trichloride dropwise, and connect the tail gas absorption device to absorb irritating HCl gas during the dropwise addition. After the phosphorus trichloride was added dropwise, the temperature of the three-neck flask was raised slowly to 95-100°C. It was observed that the reaction product was evenly dispersed in the solvent without lumps. The temperature was kept at 95-10...

Embodiment 2

[0049] Raw material name Amount Mole number Mole ratio

[0050] 3-(N-Methyl-N-n-pentylamine) propionate hydrochloride 100 g 0.477 1

[0051] Phosphorus trichloride 92 grams 0.662 1.39

[0052] Phosphorous acid 121 grams 1.479 3.1

[0053] Acetonitrile 800g

[0054] Sodium hydroxide (50%) about 100mL

[0055] water 400mL

[0056] crafting process:

[0057] In a 2L three-necked flask equipped with a reflux device, 100 g of 3-(N-methyl N-pentylamino) propionate hydrochloride, 121 g of phosphorous acid, and 800 g of acetonitrile were added. Stir, slowly raise the temperature to 70°C, add 92 grams of phosphorus trichloride dropwise, and connect the tail gas absorption device to absorb irritating HCl gas during the dropwise addition. After the phosphorus trichloride was added dropwise, the temperature of the three-neck flask was raised slowly to 95-100°C. It was observed that the reaction product was evenly dispersed in the solvent without lumps. The temperature was kept at 95...

Embodiment 3

[0064] Raw material name Amount Mole number Mole ratio

[0065] 3-(N-Methyl-N-n-pentylamine) propionate hydrochloride 100 g 0.477 1

[0066] Phosphorus trichloride 83 grams 0.596 1.25

[0067] Phosphorous acid 121 grams 1.479 3.1

[0068] Acetonitrile 600g

[0069] Sodium hydroxide (50%) about 100mL

[0070] water 400mL

[0071] crafting process:

[0072] In a 2L three-neck flask equipped with a reflux device, 100 g of 3-(N-methyl-N-pentylamino) propionate hydrochloride, 121 g of phosphorous acid, and 600 g of acetonitrile were added. Stir, slowly raise the temperature to 70°C, add 83 grams of phosphorus trichloride dropwise, and connect the tail gas absorption device to absorb irritating HCl gas during the dropwise addition. After the phosphorus trichloride was added dropwise, the temperature of the three-neck flask was raised slowly to 95-100°C. It was observed that the reaction product was evenly dispersed in the solvent without lumps. The temperature was kept at 95-1...

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Abstract

The invention relates to a synthetic method of sodium ibandronate, which comprises the following steps: adding 3-(N-methyl-N-n-amyl amine)propanoic acid hydrochloride, orthophosphorous acid and phosphorus trichloride into a solvent, reacting to obtain ibandronic acid, and forming the salt of the ibandronic acid and sodium hydroxide to obtain the sodium ibandronate, and is characterized in that the added solvent is acetonitrile, the acetonitrile is used as the solvent, and a reaction product can be uniformly dispersed in the solvent, thereby the defect that other solvents enable the product to be in the shape of oil blocks to enable stirring to be more difficult is overcome, so that the process can be successfully used for large-scale production; the mol ratio of the 3-(N-methyl-N-n-amyl amine)propanoic acid hydrochloride to the phosphorus trichloride is 1:1.20 to 1.39, and the usage amount of the phosphorus trichloride is reduced, so that the refinement times can be reduced, thereby the refinement loss is reduced.

Description

technical field [0001] The invention belongs to a medicine synthesis process, in particular to a synthesis process of ibandronic acid sodium. Background technique [0002] Bisphosphonate drugs are one of the hotspots in recent research in the field of medicine in the world, and their application prospects are extremely broad. [0003] Ibandronic acid sodium is the latest generation of bisphosphonate drugs, which is the third generation. It has the advantages of high efficiency, low toxicity and convenient use. It is available in oral and intravenous dosage forms. [0004] In addition to treating bone metastases of malignant tumors, ibandronate sodium can also prevent the occurrence of skeletal events after bone metastases and breast cancer bone metastases, and can prevent and treat osteoporosis. It is currently the most widely indicated bisphosphonate drug. [0005] Sodium ibandronate is clinically used to treat hypercalcemia, bone pain, and osteitis deformans caused by ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/38
Inventor 黄毅彭国强熊骏宇周恩惠
Owner 武汉同源药业有限公司
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