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Method for preparing sodium ibandronate

The technology of sodium ibandronate and ibandronic acid is applied in the field of preparation of sodium ibandronate, can solve the problems of low yield of sodium ibandronate, high production cost, many steps and the like, and achieves high purity, The effect of few reaction steps and mild reaction conditions

Active Publication Date: 2013-04-10
HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The object of the present invention is to provide a kind of sodium ibandronate and preparation method thereof, to solve the technical problems of low yield, low purity, many steps and high production cost of sodium ibandronate in the prior art

Method used

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  • Method for preparing sodium ibandronate
  • Method for preparing sodium ibandronate
  • Method for preparing sodium ibandronate

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preparation example Construction

[0034] One aspect of the present invention provides a kind of preparation method of sodium ibandronate, comprising the following steps:

[0035] 1) Bromination reaction of 3-methylaminopropionitrile with n-bromopentane in N,N-dimethylformamide solution of anhydrous potassium carbonate to obtain 3-(N-methyl-N-pentyl)amino propionitrile;

[0036] 2) Hydrolyzing 3-(N-methyl-N-pentyl)aminopropionitrile and a phase transfer catalyst under alkaline conditions to obtain 3-(N-methyl-N-pentyl)aminopropionic acid;

[0037] 3) Diphosphonate and hydrolyze 3-(N-methyl-N-pentyl)alanine, phosphorous acid, and thionyl chloride in the presence of toluene to obtain ibandronic acid;

[0038] 4) neutralizing ibandronic acid under alkaline conditions to obtain crude ibandronic acid sodium;

[0039] 5) The crude product of sodium ibandronate is subjected to a crystallization and purification step in an aqueous organic solvent to obtain sodium ibandronate.

[0040] The structural formula of above...

Embodiment 1

[0063] 1) Add 47.2g (0.562mol) of 3-methylaminopropionitrile and 150mL of N,N-dimethylformamide into a 500ml dry three-necked flask, stir well at room temperature, add 50g (0.362mol) of anhydrous potassium carbonate, Add 94.8g (0.628mol) of n-bromopentane dropwise, heat up to 40°C and stir for 2h, then add 50g (0.362mol) of anhydrous potassium carbonate, stir mechanically at 80°C for 4h, then quench with 200mL of ice water Reaction, then stirred for 1h to obtain 3-(N-methyl-N-pentyl)aminopropionitrile liquid, 3-(N-methyl-N-pentyl)aminopropionitrile liquid was extracted 3 times with 150ml of toluene respectively The organic layer was obtained, the organic layer was separated, and then washed twice with 300ml of saturated brine to obtain the organic phase, the organic phase was dried with anhydrous sodium sulfate for 2h, then filtered to obtain the filtrate, and the filtrate was concentrated under reduced pressure to obtain 85.3 g of yellow liquid 3-(N-methyl-N-pentyl)aminopropi...

Embodiment 2

[0069]1) Add 47.2g (0.562mol) of 3-methylaminopropionitrile and 150mL N,N-dimethylformamide into a 500ml dry three-necked flask, stir well at room temperature, add 100g (0.724mol) of anhydrous potassium carbonate, drop Add 94.8g (0.628mol) of n-bromopentane, heat up to 40°C and stir for 2h, then heat up to 80°C for 4h, then quench the reaction with 200mL of ice water, and stir for 1h to obtain 3-(N- Methyl-N-pentyl)aminopropionitrile liquid and 3-(N-methyl-N-pentyl)aminopropionitrile liquid were extracted three times with 150ml of toluene solution to obtain an organic layer. The organic layer was washed twice with 300 ml of saturated brine to obtain an organic phase. The organic phase was dried with anhydrous sodium sulfate for 2 h, and then filtered to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain 82.5 g of light yellow 3-(N-methyl-N-pentyl)aminopropionitrile liquid with a slightly pungent smell.

[0070] 2) In a 500ml three-necked flask,...

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Abstract

The invention provides a method for preparing sodium ibandronate. The method comprises the following steps of: performing amyl reaction on 3-methylamino propionitrile and n-bromopentane in an N,N-dimethylformamide solution of anhydrous potassium carbonate to obtain 3-(N-methyl-N-amyl) aminopropionitrile; performing hydrolysis reaction on the 3-(N-methyl-N-amyl) aminopropionitrile and a phase transfer catalyst under an alkaline condition to obtain 3-(N-methyl-N-amyl) aminopropionic acid; and performing diphosphonic acidification and hydrolysis reaction on the 3-(N-methyl-N-amyl) aminopropionic acid, phosphorous acid and thionyl chloride in the presence of toluene to obtain ibandronic acid; and performing neutralization reaction on the ibandronic acid under an alkaline condition to obtain the sodium ibandronate. By adopting the method, the technical problems of low yield, low purity, more steps and high production cost of the sodium ibandronate in the prior art are solved.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a preparation method of ibandronic acid sodium. Background technique [0002] Ibandronate sodium, the chemical name is 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid monosodium salt monohydrate, molecular formula: C 9 h 22 NO 7 P 2 Na·H 2 O, molecular weight: 359.24, its structural formula is as follows: [0003] [0004] Ibandronate sodium is mainly used for the treatment of hypercalcemia caused by malignant tumors and bone metastasis of multiple myeloma and solid tumors, and is also expected to be used for the treatment of osteoporosis. Ibandronate sodium is a representative drug of the third generation of bisphosphonate bone resorption drugs, which can specifically act on bone tissue, inhibit osteoclast activity, and induce osteoclast apoptosis. [0005] In the prior art, the preparation of sodium ibandronate mostly adopts multi-step reaction to synthesize 3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/38
Inventor 张庆华陈波
Owner HUNAN FANGSHENG PHARMACEUTICAL CO LTD
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