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Preparation method of sodium ibandronate

A technology of sodium ibandronate and propionate hydrochloride, applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, blood diseases, etc., can solve the problem of low chloride and phosphite content , high chloride and phosphite content, etc., to achieve the effect of easy industrial production, high product purity and long cycle

Inactive Publication Date: 2015-05-27
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to overcome the shortcomings of high chloride and phosphite content in ibandronic acid sodium prepared by the existing preparation method of ibandronic acid sodium, and to provide a product containing extremely low chloride and phosphite content. The preparation method of sodium ibandronate,

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1 comparative test

[0026] The preparation of sodium ibandronate of the present invention

[0027] Add 10.5g (0.050mol) of 3-(N-methyl-n-pentylamino) propionate hydrochloride, 10.3g (0.125mol) of phosphorous acid and 50ml of chlorobenzene into the reaction flask, stir and heat to 80°C, add three Phosphorus chloride 11ml (0.125mol), after dripping, keep warm for 9 hours, discard the supernatant chlorobenzene solution, add 0.1mol / L hydrochloric acid solution 160ml, heat to 90°C and keep warm for 10 hours, then filter, and concentrate the filtrate under reduced pressure , 42ml of purified water to dissolve the residue, add petroleum ether (60-90℃) to extract twice, 21ml each time, discard the petroleum ether layer, collect the water layer, concentrate to obtain the residue ibandronic acid, add 42ml of purified water to dissolve and use Adjust the pH to 4.3 with 30% sodium hydroxide solution, add 42 ml of tetrahydrofuran dropwise, crystallize, and filter to ...

Embodiment 2

[0035] Example 2 Stability test

[0036] Take the samples of Example 1 (batch number: 100601 batches) and reference example 1 (100102 batches), put them in a petri dish, spread them into a thin layer ≤ 5mm thick, and place them in high temperature (60°C, 40°C), high humidity (25 ℃ RH92.5%, 25℃ RH75%±5%) for 10 days, samples were taken on the 5th and 10th day. The results are shown in Table 1 below.

[0037] Table 1 The results of the experimental investigation on the influencing factors of ibandronate sodium

[0038]

[0039]Conclusion: The samples of Example 1 and Reference Example 1 were placed at high temperature 60°C, 40°C and high humidity RH75%, 92.5% for 5 and 10 days respectively. The appearance, chloride, There was no significant change in the indicators of phosphite, maximum single impurity and total impurity of related substances, content, etc.; chloride, phosphite, maximum single impurity and total impurity of related substances were higher in the samples of...

Embodiment 3

[0040] Example 3 Preparation of Sodium Ibandronate

[0041] Add 21g (0.10mol) of 3-(N-methyl-n-pentylamino) propionate hydrochloride, 20.5g (0.25mol) of phosphorous acid and 210ml of chlorobenzene into the reaction flask, stir and heat to 90°C, and drop trichloro Phosphate 22ml (0.25mol), after dripping, keep warm for 12 hours, discard the supernatant chlorobenzene solution, add 0.1mol / L hydrochloric acid solution 420ml, heat to 80°C and keep warm for 12 hours, filter, evaporate the solvent under reduced pressure , 84ml of purified water to dissolve the residue, add petroleum ether (30-60°C) to extract twice 84ml each time, collect the water phase and concentrate to obtain the residue, add 84ml of purified water to dissolve, adjust the pH to 4.0 with 30% sodium hydroxide solution, 84 ml of tetrahydrofuran was added dropwise, crystallized, and 26.3 g of sodium ibandronate was obtained by filtration, with a yield of 73.2%.

[0042] Volumetric titration test: content 99.5%; HP...

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Abstract

The invention relates to the technical field of pharmaceutical chemistry, particularly relates to a method of pharmaceutical synthesis, and specifically relates to a preparation method of sodium ibandronate. To overcome the disadvantages of high content of chlorides and phosphites in sodium ibandronate prepared by a conventional preparation method of sodium ibandronate, the preparation method of sodium ibandronate with extremely low content of chlorides and phosphites is provided. In the preparation method, 3-(N-methylpentylamino) propionic acid hydrochloride, phosphorus trichloride and phosphorous acid are employed as raw materials and reacted in a chlorobenzene solvent, so as to obtain sodium ibandronate with extremely low content of the chlorides and the phosphites. The obtained sodium ibandronate can not only meet impurity control standards of the chlorides and the phosphites in a sodium ibandronate crude drug, but also prevent low yield, long period and huge harm to human body and environment which are brought by a lot of refining steps.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a method for synthesizing medicines, in particular to a preparation method for sodium ibandronate. Background technique [0002] Ibandronate Sodium (Ibandronate Sodium) is a new generation of bisphosphonate drugs after Alendronate Sodium, Pamidronate Sodium, Clodronate Sodium and Itidronate Sodium. The chemical name is: [ 1-Hydroxy-3-(N-methyl-N-pentylamino)propylene]bisphosphonic acid monosodium salt monohydrate, its structural formula is: [0003] [0004] Molecular formula: C 9 h 22 NNaO 7 P 2 ·H 2 o [0005] Molecular weight: 359.23 [0006] Ibandronate sodium is the third-generation bisphosphonate drug, an anti-bone resorption agent developed by Hoffmamn-La Roche Company. It was first launched in Germany and Austria in 1996. It is mainly used clinically for the treatment of Hypercalcemia due to bone metastatic malignancy and treatment of osteoporosis i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/38A61P7/00A61P19/10
Inventor 赵俊宗在伟李谢
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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