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Preparation method of (4S)-3, 6, 9-triaza-3, 6, 9-tri(carboxymethyl)-4-(4-ethoxy benzyl)undecanedioic acid

A technology of ethoxybenzyl and triaza, which is applied in the field of -3, can solve the problems of being unsuitable for industrial production, achieve the effect of being suitable for industrial production and avoiding chromatographic steps

Active Publication Date: 2014-11-05
安徽昊帆生物有限公司
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Problems solved by technology

Not suitable for industrial production

Method used

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  • Preparation method of (4S)-3, 6, 9-triaza-3, 6, 9-tri(carboxymethyl)-4-(4-ethoxy benzyl)undecanedioic acid
  • Preparation method of (4S)-3, 6, 9-triaza-3, 6, 9-tri(carboxymethyl)-4-(4-ethoxy benzyl)undecanedioic acid

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Embodiment 1

[0025] Synthesis of (4S)-3,6,9-triaza-3,6,9-tris(nitrilemethyl)-4-(4-ethoxybenzyl)undecanedinitrile

[0026] Add (4S)-1-(4-ethoxybenzyl)-3-azopentane-1,5-diamine trihydrochloride (34.6g, 0.1moL, 1.0eq. ), THF346mL, water (70mL, 2P) and potassium carbonate (110.4g, 0.8moL, 8.0eq.). After the solution was stirred and clarified, bromoacetonitrile (89.96g, 0.75moL, 7.5eq.) was added dropwise at room temperature. After the dropwise addition, the temperature was raised to 80°C and refluxed for 6 hours. Extract 300mL×2, collect the organic layer, wash 200mL×1 with saturated brine, and dry over anhydrous sodium sulfate. Filtered, evaporated to dryness with a water pump, and recrystallized from ethyl acetate to obtain (4S)-3,6,9-triaza-3,6,9-tris(nitrilemethyl)-4-(4-ethane) as a light yellow solid Oxybenzyl)undecanedinitrile (26 g, 60% yield).

[0027] 1 H NMR (400MHz, CDCl 3 ): δ=1.31-1.35 (t, 3H, CH 3 ), 2.30-2.73 (m, 8H, 4CH 2 ), 3.25(m, 1H, CH), 3.48(s, 10H, 5CH 2 ), 3.95-4...

Embodiment 2

[0029] Synthesis of (4S)-3,6,9-triaza-3,6,9-tris(nitrilemethyl)-4-(4-ethoxybenzyl)undecanedinitrile

[0030] Add (4S)-1-(4-ethoxybenzyl)-3-azopentane-1,5-diamine (34.6g, 0.1moL, 1.0eq.), THF346mL to a 1L three-necked flask, Water 70 mL, and sodium carbonate (110 g, 0.8 moL, 8.0 eq.). After the solution was stirred and clarified, chloroacetonitrile (56.2g, 0.75moL, 7.5eq.) was added dropwise at room temperature. After the dropwise addition, the temperature was raised to 80°C and refluxed for 5 hours. Extract 300mL×2, collect the organic layer, wash 200mL×1 with saturated brine, and dry over anhydrous sodium sulfate. Filtered, evaporated to dryness with a water pump, and recrystallized from ethyl acetate to obtain (4S)-3,6,9-triaza-3,6,9-tris(nitrilemethyl)-4-(4-ethane) as a light yellow solid Oxybenzyl)undecanedinitrile (25 g, 57% yield).

[0031] 1 H NMR (400MHz, CDCl 3 ): δ=1.31-1.35 (t, 3H, CH 3 ), 2.302.73 (m, 8H, 4CH 2 ), 3.25(m, 1H, CH), 3.48(s, 10H, 5CH 2 ), 3.95...

Embodiment 3

[0033]Synthesis of (4S)-3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid -3,6,9-Triaza-3,6,9-tris(nitrilemethyl)-4-(4-ethoxybenzyl)undecanedinitrile (26g, 0.06moL, 1.0eq.) Add methanol (390mL, 15P) to a 1L three-neck flask to dissolve, then add sodium hydroxide (60g, 1.5moL, 25eq.) and water (13mL, 0.5P) solution, and heat up and reflux for 24 hours. After the reaction, concentrate the reaction solution, beat with ethanol to remove excess sodium hydroxide, then dissolve it in 80mL of water, adjust the pH value of the solution to 2.0 with 1N HCl solution under ice bath, filter, wash with water, dry with hot water (100°C) recrystallization to give white solid (4S)-3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecane Diacid (19 g, 60% yield).

[0034] 1 H NMR (400MHz, DMSO): = 1.31-1.35(t, 3H, CH 3 ), 2.34-2.83 (m, 8H, 4CH 2 ), 3.24(m, 1H, CH), 3.12-3.37(s, 10H, 5CH 2 ), 3.91-4.01 (m, 2H, CH 2 ), 6.79-6.81 (d, 2H, J=8.0Hz, ArH), 7.09...

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Abstract

The invention provides a preparation method of (4S)-3, 6, 9-triaza-3, 6, 9-tri(carboxymethyl)-4-(4-ethoxy benzyl)undecanedioic acid. The method includes: taking (4S)-1-(4-ethoxy benzyl)-3-azapentane-1, 5-diamine or its hydrochloride as the starting material, reacting the starting material with haloacetonitrile under the catalysis of an anhydrous carbonic acid alkali metal salt in an organic solvent to obtain 4S-3, 6, 9-triaza-3, 6, 9-tri(cyanomethyl)-4-(4-ethoxy benzyl)undecanedinitrile solid, using ethyl acetate to perform recrystallization purification on the solid, and directly conducting hydrolysis to obtain (4S)-3, 6, 9-triaza-3, 6, 9-tri(carboxymethyl)-4-(4-ethoxy benzyl)undecanedioic acid. Complicated chromatographic treatment and ion exchange column chromatography purification methods are avoided in the invention. Compared with traditional methods, the method provided by the invention lowers the production cost, is simple to operate, and is suitable for industrialized production.

Description

technical field [0001] The present invention relates to the technical field of chemical synthesis, more particularly to (4S)-3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)deca A method for the preparation of alkanedioic acid. Background technique [0002] Magnetic resonance imaging (MRI) technology has been widely used in biological and medical fields, and has become a common medical diagnosis method. In order to enhance the contrast and clarity of images, appropriate contrast agents are often used in clinical MRI, and about 30% of MRI require the use of contrast agents. An important research direction of MRI contrast agents in the world is to develop contrast agents with organ and tissue targeting, which can enrich the contrast agents in specific organs or tissues, improve the contrast effect, reduce the dosage and reduce the toxicity. Gadoxetic acid disodium (Gadoxetic acid disodium) is formed by chelating paramagnetic gadolinium ions and lipophilic p-ethoxybe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/16
Inventor 蒋兆琴吕敏杰
Owner 安徽昊帆生物有限公司
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