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A kind of synthetic method of phosphoric acid citric acid derivative

A technology of citric acid phosphoric acid and derivatives, which can be used in drug combinations, phosphorus organic compounds, bone diseases, etc., can solve the problems of high price and unsuitable for large-scale synthesis, and achieve the effects of excellent quality, excellent product quality, and cost reduction.

Inactive Publication Date: 2016-04-20
天津特安化学科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The last step of this method uses ion exchange resin, which is expensive and not suitable for large-scale synthesis.

Method used

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  • A kind of synthetic method of phosphoric acid citric acid derivative
  • A kind of synthetic method of phosphoric acid citric acid derivative
  • A kind of synthetic method of phosphoric acid citric acid derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0027] First step response:

[0028]

[0029] Dissolve 100g of methoxyphosphorus dichloride in 280ml of anhydrous ether, cool to -20°C, the mass ratio of methoxyphosphorus dichloride to anhydrous ether is 1:2, and add dropwise to the solution containing 100g of diiso In the ether solution of propylamine, the mass ratio of diisopropanol to ether is 1:2, the mass ratio of methoxyphosphorous dichloride to diisopropanol is 1:1, react at room temperature for 2 hours, filter to remove the precipitate, and the filtrate Cool to -20°C, slowly add 50g N, N-diisopropylethylamine and 50g benzyl alcohol, the mass ratio of methoxyphosphorus dichloride to N, N-diisopropylethylamine is 1:0.5, and The mass ratio of benzyl alcohol is 1: 0.5, and reaction mixture rises to room temperature in 1 hour, stirs and reacts for 2 hours, filters the salt that reaction generates, and filter cake is washed with 200ml ether, and filtrate decompression evaporates solvent wherein, and with sherwood oil / T...

Embodiment 2

[0037] First step response:

[0038] Dissolve 1kg of methoxyphosphorus dichloride in 3.5L of anhydrous ether, cool to -20°C, the mass ratio of methoxyphosphorus dichloride to anhydrous ether is 1:2.5, and add dropwise to the solution containing 1.5kg In the ether solution of diisopropylamine, the mass ratio of diisopropylamine to ether is 1:2.5, the mass ratio of methoxyphosphorus dichloride to diisopropanol is 1:1.5, react at room temperature for 2 hours, filter to remove the precipitate, The filtrate was cooled to -20°C, slowly added 700g N, N-diisopropylethylamine and 700g benzyl alcohol, the mass ratio of methoxyphosphorus dichloride and N, N-diisopropylethylamine was 1:0.7, The mass ratio with benzyl alcohol is 1: 0.7, the reaction mixture is raised to room temperature in 1 hour, stirred and reacted for 2 hours, the salt generated by the reaction is filtered off, the filter cake is washed with 800ml ether, the filtrate is evaporated under reduced pressure to remove the so...

Embodiment 3

[0044] First step response:

[0045] Dissolve 500g of methoxyphosphorus dichloride in 2.1L of anhydrous ether, cool to -20°C, the mass ratio of methoxyphosphorus dichloride to anhydrous ether is 1:3, add dropwise to the solution containing 1kg of dichloride In the ether solution of isopropylamine, the mass ratio of diisopropylamine to ether is 1:3, the mass ratio of methoxyphosphorous dichloride to diisopropanol is 1:2, react at room temperature for 2 hours, filter to remove the precipitate, and the filtrate Cool to -20°C, slowly add 750g N, N-diisopropylethylamine and 750g benzyl alcohol, the mass ratio of methoxyphosphorus dichloride to N, N-diisopropylethylamine is 1: 1.5, and The mass ratio of benzyl alcohol is 1: 1.5, and reaction mixture rises to room temperature in 1 hour, stirs and reacts for 2 hours, filters the salt that reaction generates, and filter cake is washed with 800ml ether, and filtrate decompression evaporates solvent wherein, with sherwood oil / The crude...

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Abstract

The invention provides a method for preparing a phosphoric citrate derivative. The method comprises the steps of dripping an ether solution of diisopropylamine into an ether solution of methoxyl phosphorus dichloride with the temperature of -20 DEG C, reacting at room temperature, cooling a filtrate, adding N,N-diisopropylethylamine and benzyl alcohol, reacting at room temperature, evaporating to remove a solvent, and purifying so as to obtain an oily matter; dripping a dichloromethane solution of tribenzyl citrate and tetrazole into a dichloromethane solution of the oily matter, mixing for 2 hours, then, cooling, and adding a dichloromethane solution of m-chloroperoxybenzoic acid; an hour later, diluting a mixture by using dichloromethane, and washing sequentially by using sodium sulfite, sodium bicarbonate and salt solutions; evaporating to remove a solvent, and purifying so as to obtain a colorless oily product; and reacting a mixture of the oily product, a Pd / C catalyst, methanol and hydrogen gas at room temperature, and adding a methanol solution of sodium methoxide into a filtrate at the temperature of 0-4 DEG C, thereby obtaining a white solid phosphoric citrate derivative. The method is mild in conditions and high in yield and does not need special equipment.

Description

technical field [0001] The invention relates to a method for synthesizing citric acid phosphoric acid derivatives, in particular to medicinal salts and combination compounds thereof. Background technique [0002] Osteoarthritis is a degenerative joint disease in which cartilage and bone are primarily affected. Osteoarthritis damages and wears down the cartilage, affecting joints on one side of the body, causing joint swelling and pain. [0003] This phosphocitrate derivative is a natural biomolecule and is non-toxic. It inhibits the appearance of crystals, thereby preventing the deposition of Ca2+ containing crystals in cartilage. The American journal J.Org.Chem.2007, 72, 1470-1471 introduced the synthesis of compounds with similar structures, but the synthesis steps are cumbersome and consume a lot of energy, which is not suitable for mass production. The phosphocitric acid derivatives synthesized in this paper can be used for fracture osteoarthritis and prevention of me...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/09A61P19/02A61P19/10
Inventor 刘杨陈禹全祝士忠李茜
Owner 天津特安化学科技有限公司
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