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Method for synthesizing sodium ibandronate

A technology of sodium ibandronate and alkyl ibandronate, which is applied in a new synthesis field, can solve the problems of cumbersome operation and long preparation route, and achieve the effect of improving safety, less steps and easy operation

Active Publication Date: 2011-06-15
南京恒生制药有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] No matter it is the above-mentioned route one or route two, all use N-methyl n-pentylamine as the key intermediate, its preparation route is all long, the operation is more loaded down with trivial details, and the last step all needs to use PCl 3 , POCl 3 and PCl 5 Highly toxic reagents such as chlorobenzene and other highly toxic solvents are also used in the reaction

Method used

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  • Method for synthesizing sodium ibandronate
  • Method for synthesizing sodium ibandronate
  • Method for synthesizing sodium ibandronate

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preparation example Construction

[0036] The following generally describes the preparation of ibandronate sodium

[0037] 1. Synthesis of N-methyl-β-alanine methyl ester

[0038] Add methylamino alcohol solution to the reaction device and slowly add methyl acrylate dropwise at -10--5°C. After the dropwise addition, continue to react at -10--5°C for 24 hours. After the reaction is completed, remove it under reduced pressure at room temperature Solvent and unreacted methylamine, the residue was distilled under reduced pressure, and the distillation conditions were 40-50°C, 4-5 torr fractions were collected.

[0039] 2. Synthesis of [1-hydroxy-3-methylaminopropylene] bisphosphate tetraalkyl ester

[0040]

[0041] Add N-methyl-β-alanine methyl ester, formula (V) compound, dialkyl phosphinate, reaction solvent in the reaction device, heat and reflux for reaction, after the reaction is completed, add water to stir, and pour the liquid into the liquid funnel, extracted with ethyl acetate, collected the organic ...

Embodiment 1

[0045] Embodiment 1: bisphosphonic acid monosodium salt

[0046]1. Synthesis of N-methyl-β-alanine methyl ester

[0047] Add methylamino alcohol solution (150ML, 1.5mol) into a 500ml reaction flask and slowly add methyl acrylate (75g, 0.87mol) dropwise at -10--5°C. The reaction was continued for 24 hours at low temperature. After the reaction was completed, the solvent and unreacted methylamine were removed under reduced pressure at room temperature, and the residue was distilled under reduced pressure. The distillation conditions were 40-45 ° C, 86 g of fractions at 4-5 torr, and the yield was 84.4%. 98.2% purity.

[0048] 2. Synthesis of tetramethyl [1-hydroxy-3-methylaminopropylene] diphosphate

[0049] In a 1000ml reaction flask, add 86g (0.734mol) of N-methyl-β-alanine methyl ester, 5g of sodium methoxide, dimethyl phosphinate (177.7g, 1.615mol), 250ml of anhydrous methanol, and heat to reflux React for 3 hours, the reaction is over, add 300ml of water, stir for 0.5 ho...

Embodiment 2

[0055] 1. Synthesis of [1-hydroxy-3-methylaminopropylene] tetraethyl diphosphate

[0056] Add 86 g (0.734 mol) of N-methyl-β-alanine methyl ester, 7 g sodium ethoxide, diethyl phosphinate (262.2 g, 1.9 mol), and 200 ml absolute ethanol into a 1000 ml reaction flask, and heat to reflux React for 3 hours, the reaction is over, add 280ml of water, stir for 0.5 hours, pour the liquid into a separatory funnel, extract with 300ml of ethyl acetate, collect the organic layer, wash with 200ml of saturated brine, and concentrate the organic phase under reduced pressure to obtain [1- 198 g of tetraethyl hydroxy-3-methylaminopropylene] diphosphate, the yield is 74.7%.

[0057] 2. Synthesis of [1-hydroxyl-3-(N-methyl-N-n-pentylamino)propylene]bisphosphonic acid monosodium salt monohydrate (sodium ibandronate)

[0058] Pour 198 g (0.55 mol) of [1-hydroxy-3-methylaminopropylene] tetraethyl diphosphate into the reaction flask, add 200 ml of ethanol, heat to reflux, and slowly drop in 63.95 g...

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Abstract

The invention discloses a method for synthesizing sodium ibandronate. The sodium ibandronate is prepared by the following steps: reacting an intermediate compound (III) with halogenated n-pentane; and then hydrolyzing and acidifying so as to obtain the sodium ibandronate, wherein in the formula (III), R1 is C1-4 alkyl. The method has the characteristics that the reaction steps are less, the used reagent is small in toxicity, the safety is good, and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new synthesis method of ibandronic acid sodium. Background technique [0002] Sodium ibandronate is a third-generation bisphosphonate drug, which is an analogue of endogenous pyrophosphate; it can strongly inhibit the activity of osteoclasts and bone resorption, with definite curative effect, long-lasting effect and relatively low side effects. Small, gradually become the drug of choice for the treatment of hypercalcemia complicated by malignant tumors and bone pain caused by osteolytic cancer metastasis. The structural formula of ibandronate sodium is as follows: [0003] [0004] There are many synthetic routes of sodium ibandronate reported in the literature, which were summarized in Chinese Journal of Pharmaceuticals 2010, 41(2) 151-153. [0005] [0006] Among them, there are mainly two routes that are more widely used. [0007] Route 1: Benzaldehyde...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/38
Inventor 王卓异李德富黄安民何国新
Owner 南京恒生制药有限公司
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