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Method for preparing zoledronic acid and sodium salt thereof by utilizing phase transfer catalyst

A technology of phase transfer catalyst and zoledronic acid, which is applied in the direction of chemical instruments and methods, physical/chemical process catalysts, organic compound/hydride/coordination complex catalysts, etc., can solve the problem of poor yield of product zoledronic acid High, gradual thickening, unsatisfactory, etc., to achieve good industrial application prospects, increased yield, and good product quality.

Active Publication Date: 2011-05-25
BENGBU BBCA MEDICINE SCI DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In its patent description, diglyme, monoglyme or their mixtures are used as solvents to try to solve the problem of gradual thickening of the two-phase system, but the final yield is only about 28%, which is not ideal
The step-by-step synthesis of zoledronic acid method of CN1472215A and the step-by-step synthesis of zoledronic acid method of CN1693308A, related domestic unauthorized patents, have actually encountered similar problems, and finally caused the yield of the product zoledronic acid to be low, about 20 ~30% or so

Method used

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  • Method for preparing zoledronic acid and sodium salt thereof by utilizing phase transfer catalyst
  • Method for preparing zoledronic acid and sodium salt thereof by utilizing phase transfer catalyst
  • Method for preparing zoledronic acid and sodium salt thereof by utilizing phase transfer catalyst

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Add 15g of imidazole and 200ml of 1,4-dioxane into a 500ml three-necked flask, stir at room temperature to dissolve. Add 10g of sodium hydroxide and 3g of benzyltriethylammonium chloride (phase transfer catalyst TEBA), stir evenly, then add about 40ml of excess ethyl chloroacetate dropwise, and the dropwise addition is completed after 0.5h. TLC showed the degree of progress of the reaction (the developer was ethyl acetate:petroleum ether=5:1, 10% phosphomolybdic acid was used as the developer), and the reaction was complete after 2 hours.

[0026] At room temperature, after adding 36g of phosphorous acid and stirring to dissolve, slowly add 38ml of excess phosphorus trichloride dropwise, and the dropwise addition is completed after 1 hour. After 4 hours, TLC showed that the reaction was complete, and the reaction was allowed to stand at room temperature overnight.

[0027] Turn on mechanical stirring, slowly add 70ml of distilled water dropwise (to neutralize excess ph...

Embodiment 2

[0031] Add 15g of imidazole and 200ml of tetrahydrofuran into a 500ml three-necked flask, stir at room temperature to dissolve. Add 9.7g of sodium hydroxide and 2.3g of benzyltriethylammonium chloride (phase transfer catalyst TEBA), stir well, then add about 35ml of excess ethyl chloroacetate dropwise, and dropwise complete after 0.5h. TLC showed the degree of progress of the reaction (the developer was ethyl acetate:petroleum ether=5:1, 10% phosphomolybdic acid was used as the developer), and the reaction was complete after 2 hours.

[0032] At room temperature, after adding 36.5g of phosphorous acid and stirring to dissolve, slowly add 40ml of excess phosphorus trichloride dropwise, and the dropwise addition is completed after 1.5h. After 4 hours, TLC showed that the reaction was complete, and the reaction was allowed to stand at room temperature overnight.

[0033] Turn on mechanical stirring, slowly add 100ml of distilled water dropwise (to neutralize excess phosphorus tr...

Embodiment 3

[0036] Add 15g of imidazole and 200ml of 1,4-dioxane into a 500ml three-necked flask, stir at room temperature to dissolve. Add 10.5g of sodium hydroxide and 4.5g of benzyltriethylammonium chloride (phase transfer catalyst TEBA), stir evenly, then add about 45ml of excess ethyl chloroacetate dropwise, and the dropwise addition is completed after 0.8h. TLC showed the degree of progress of the reaction (the developer was ethyl acetate:petroleum ether=5:1, 10% phosphomolybdic acid was used as the developer), and the reaction was complete after 2 hours.

[0037] At room temperature, after adding 40 g of phosphorous acid and stirring to dissolve, slowly add 38 ml of excess phosphorus trichloride dropwise, and the dropwise addition is completed after 1 hour. After 4 hours, TLC showed that the reaction was complete, and the reaction was allowed to stand at room temperature overnight.

[0038]Turn on mechanical stirring, slowly add 70ml of distilled water dropwise (to neutralize exce...

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Abstract

The invention relates to a phase transfer catalyst used for preparing zoledronic acid and sodium salt thereof, and a method for preparing the zoledronic acid and sodium salt thereof by utilizing the phase transfer catalyst. Compared with the prior art, due to the adoption of the phase transfer catalyst, the method has the advantages that: the extent of reaction is accelerated, the reaction yield is high, and the total synthesis yield is improved by about 60 percent; and compared with the conventional method, the method at least doubles the yield at one time and has significance for productioninnovation of the zoledronic acid. Moreover, in the synthesis method, the zoledronic acid is synthesized by a one-pot method, and the method ensures high product quality and yield and has good industrial application prospect.

Description

technical field [0001] The present invention relates to the field of chemical synthesis and pharmacy, specifically, it relates to selecting a phase transfer catalyst for preparing zoledronic acid and its sodium salt, and a method for preparing zoledronic acid and its sodium salt using the phase transfer catalyst . Background technique [0002] Zoledronic acid, whose chemical name is [1-hydroxy-2-(1-imidazolyl) ethylidene] diphosphate monohydrate, is a third-generation heterocyclic bisphosphonic acid drug for the treatment of hypercalcemia. Zoledronic acid is a diphosphate compound that specifically acts on bone. It can inhibit bone resorption caused by increased osteoclastic activity, but has no adverse effects on bone formation, bone mineralization and mechanical properties. It is mainly used to treat hypercalcemia (TIH or HCM) caused by tumors, to inhibit bone metastasis caused by tumors, and osteoporosis in menopausal women. Clinical trials have shown that this product ...

Claims

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Application Information

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IPC IPC(8): C07F9/6506B01J31/02
Inventor 胡媛张亚郑爱
Owner BENGBU BBCA MEDICINE SCI DEV
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