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Zoledronic acid intermediate compound

A technology for zoledronic acid and compound, applied in the field of zoledronic acid intermediate compounds, can solve the problems of low environmental protection, containing bisphosphonate impurities, long reaction period and the like, and achieves improved safety, simple and controllable synthesis Effect

Pending Publication Date: 2021-03-30
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Aiming at the problems of low environmental protection, long reaction cycle and containing bisphosphonate impurities in the current synthesis process of zoledronic acid, the present invention provides a zoledronic acid intermediate compound I and a preparation method of the compound The raw materials of the method are simple and easy to obtain, the reaction conditions are mild, and the operation process is simple; the preparation of zoledronic acid by using the compound has high purity and yield, and does not contain bisphosphonate impurities

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0057] Add imidazole (68.00g, 1mol), potassium carbonate (276.43g, 2mol), and tetrabutylammonium bromide (0.97g, 0.003mol) into acetonitrile (1000ml) in sequence, stir and reflux, and add ethyl dichloroacetate dropwise at the same time (54.95g, 0.35mol), after the reflux reaction is completed, filter, the filter cake is beaten and washed with acetonitrile (300ml×3), the organic phases are combined, the solvent is removed by rotary evaporation under reduced pressure, then absolute ethanol (2000ml) is added, stirred, filtered, Spin-dried to obtain 72.45g oily liquid compound 2,2-imidazole ethyl acetate, yield 93.98%;

[0058] Add concentrated hydrochloric acid (215ml) into 2,2-imidazole ethyl acetate (72.45g), stir and reflux, after the reaction is complete, spin dry, then add absolute ethanol for beating and washing (100ml×2), and dry to obtain 73.11g of white solid Compound 2,2-imidazole acetic acid hydrochloride, yield 97.21%;

[0059] Add 73.11g of 2,2-imidazole acetic acid...

Embodiment 2

[0062] Add imidazole (68.00g, 1mol), triethylamine (101.12g, 1mol), and iodine (1.27g, 0.005mol) into 1,4-dioxane (1000ml) in turn, stir and reflux, and drop dichloro Ethyl acetate (31.4g, 0.2mol), after the reflux reaction is completed, filter, filter cake is washed with acetonitrile (300ml×3), combine the organic phases, remove the solvent by rotary evaporation under reduced pressure, then add absolute ethanol (2000ml), stir , filtered, and spin-dried to obtain 39.83g oily liquid compound 2,2-imidazole ethyl acetate, yield 90.42%;

[0063] Add concentrated hydrochloric acid (80ml) into 2,2-imidazole ethyl acetate (39.83g), stir and reflux, after the reaction is complete, spin dry, then add absolute ethanol for beating and washing (100ml×2), and dry to obtain 39.92g of white solid Compound 2,2-imidazole acetic acid hydrochloride, yield 96.55%;

[0064] Add 39.92g of 2,2-imidazole acetic acid hydrochloride into 300ml of trifluoroacetic acid, add 85.55g of 85% phosphoric acid ...

Embodiment 3

[0067] Add imidazole (68.00g, 1mol), sodium carbonate (423.96, 4mol), cetyltrimethylammonium bromide (0.73g, 0.002mol) in dimethyl sulfoxide (1000ml) successively, stir and reflux, while Ethyl dichloroacetate (62.80g, 0.4mol) was added dropwise, the reflux reaction was completed, filtered, the filter cake was washed with acetonitrile (300ml×3), the organic phases were combined, the solvent was removed by rotary evaporation under reduced pressure, and then absolute ethanol ( 2000ml), stirred, filtered, and spin-dried to obtain 79.44g oily liquid compound 2,2-imidazole ethyl acetate, yield 90.17%;

[0068] Add concentrated hydrochloric acid (318ml) into 2,2-imidazole ethyl acetate (79.44g), stir and reflux, after the reaction is complete, spin dry, then add absolute ethanol for beating and washing (100ml×2), and dry to obtain 79.98g of white solid Compound 2,2-imidazole acetic acid hydrochloride, yield 96.99%;

[0069] Add 79.98g of 2,2-imidazole acetic acid hydrochloride into ...

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a zoledronic acid intermediate compound. According to the method, 2,2-bis-substituted acetate and imidazole are taken as initial raw materials, and a 2,2-imidazole acetic acid hydrochloride intermediate is synthesized through substitution reaction and hydrolysis reaction. The raw materials are simple and easy to obtain, the reaction conditions are mild, the operation process is simple and convenient, and the method is economical and environmentally friendly. The yield of zoledronic acid prepared from the intermediate compound can reach 85.27%, diphosphonic acid impurities do not exist, and the purity is as high as 99.8% or above.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a zoledronic acid intermediate compound. Background technique [0002] Zoledronic acid (Zoledronic Acid), the chemical name is 1-hydroxy-2-((1-imidazolyl)-ethylidene)-1,1-bisphosphonic acid, is a heterocyclic third party developed by Swiss Novartis company. It is a new generation of bisphosphonic acid drugs, which was first approved for marketing in Canada under the trade name Zometa in 2000, and was subsequently approved in more than 80 countries or regions including the European Union and the United States. Zoledronic acid can be used to treat hypercalcemia (HCM) caused by malignant tumors, multiple myeloma and bone metastasis of solid tumors, and has therapeutic effects on HCM caused by malignant tumors, advanced tumor metastasis and osteitis deformans. It can reduce the occurrence of bone-related events, relieve symptoms, improve the quality of l...

Claims

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Application Information

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IPC IPC(8): C07D233/56C07F9/6506
CPCC07D233/56C07F9/6506
Inventor 翟立海杨宇谢印杰徐杰
Owner LUNAN PHARMA GROUP CORPORATION
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