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S-1-(4-ethoxybenzyl)-3-azapentane-1,5 diamine preparation method

An ethoxybenzyl and azapentane technology is applied in the preparation of carboxylic acid amides, the preparation of organic compounds, chemical instruments and methods, etc. problem, to achieve the effect of high safety, short response time and convenient operation

Active Publication Date: 2007-08-01
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the fourth step, diborane is used for the reduction of amides. Diborane is a flammable and explosive substance with high requirements for transportation and storage. The reaction time is as long as 32 hours, resulting in low equipment efficiency, high toxicity and high risk of diborane.

Method used

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  • S-1-(4-ethoxybenzyl)-3-azapentane-1,5 diamine preparation method
  • S-1-(4-ethoxybenzyl)-3-azapentane-1,5 diamine preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0014] The synthesis of embodiment 1 O-ethyl-N-boc-L-tyrosine ethyl ester:

[0015] Add N-boc-L-tyrosine ethyl ester (24.8g, 0.08mol) and 180mL DMF into a 500mL three-necked flask, stir and dissolve, then add 22.0g of anhydrous potassium carbonate and iodoethane (7mL, 0.08mol), Keep stirring at room temperature at 25°C for 20 hours, extract with ethyl acetate for post-treatment, and evaporate to dryness under reduced pressure to obtain O-ethyl-N-boc-L-tyrosine ethyl ester (25.2g, 0.075mol), which is directly used for the following without purification One-step (embodiment 2) reaction, ethyl acetate is reclaimed and used. The molar yield was 93.8% (the content detected by HPLC was 96.2%).

Embodiment 2

[0016] Example 2 Synthesis of N-(2-aminoethyl)-N-boc-O-ethyl-L-tyrosinamide:

[0017] Dissolve the O-ethyl-N-boc-L-tyrosine ethyl ester (25.2 g, 0.075 mol) obtained in the previous step (Example 1) in 100 mL of methanol, and slowly add it dropwise until anhydrous ethylenediamine is added (90g, 1.5mol) in a 500mL three-necked flask, after the dropwise addition was completed, the stirring was continued at 50°C for 20 hours. Evaporate to dryness under reduced pressure, add 60 mL of ethyl acetate to the residue, heat to dissolve and let stand, collect the precipitated white solid, and dry at 50°C to obtain N-(2-aminoethyl)-N-boc-O-ethyl- L-tyrosinamide (20 g, 0.054 mol), the molar yield was 72%, and ethyl acetate was recovered for use. mp 94-96°C, MS: 367.

Embodiment 3

[0018] Example 3 Synthesis of N-(2-aminoethyl)-O-ethyl-L-tyrosinamide:

[0019] Add N-(2-aminoethyl)-N-boc-O-ethyl-L-tyrosinamide (32g, 0.087mol) and 400mL dichloromethane into a 500mL three-necked flask, stir and dissolve, then add trifluoroacetic acid ( 22.8g, 0.2mol) was stirred at room temperature for 1 hour, concentrated and evaporated to dryness under reduced pressure to obtain N-(2-aminoethyl)-O-ethyl-L-tyrosyl (18g, 0.072mol), the molar yield was 83% , mp94~96℃ (refined product), MS: 251.

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Abstract

The invention discloses a making method of S-1-(4-ethoxy benzyl)-3-aza pantane-1, 5 diamine in the organic synthetic technical domain, which comprises the following steps: 1reacting L-tyrosine alkyl ester protected by amino and ethyl iodide catalyzed by anhydrous carbonate alkali to produce L-tyrosine alkyl ester protected by O-ethyl-amino; 2. reacting L-tyrosine alkyl ester protected by O-ethyl-amino and anhydrous ethanediamine to do ester exchange to produce O-ethyl-L-tyrosinamide protected by N-(2-amino ethyl)-amino; 3. stripping protecting group of amino through trifluoroacetic acid; 4. using aluminium lithium hydroxide to reduce; obtaining the product. The invention reduces technical difficulty with mild reacting condition, which can prepare key intermediate of Gadoxetic acid disodium (Gd-EOB-DTPA).

Description

technical field [0001] The invention relates to a preparation method of S-1-(4-ethoxybenzyl)-3-azopentane-1,5 diamine, belonging to the technical field of organic synthesis. It is a key intermediate of the liver-specific magnetic resonance contrast agent gadoxetic aciddisodium (Gd-EOB-DTPA). 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 aciddisodium) is formed by chelating...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C237/20
CPCY02P20/55
Inventor 何拥军谢敏浩罗世能刘娅灵邹霈王洪勇吴军
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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