Preparation method of S-1-(4-ethyoxylbenzyl)-3-azapentane-1,5-diaminetrihydrochloride

Abstract

The invention relates to a preparation method of S-1-(4-ethyoxylbenzyl)-3-azapentane-1,5-diaminetrihydrochloride. The preparation method comprises the following steps: adopting L-tyrosine alkyl ester as a starting raw material, carrying out alkylation reaction with bromoethane, carrying out reduction on an obtained product by use of sodium borohydride, carrying out esterification on alkyl sulfonyl chloride, reacting an obtained reaction product with ethylenediamine, removing an amino protective group by hydrogen chloride to obtain the S-1-(4-ethyoxylbenzyl)-3-azapentane-1,5-diaminetrihydrochloride. The preparation method has the advantages of simplicity in operation, mild reaction condition, safety, controllability, high reaction yield and good product purity, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of the key intermediate S-1-(4-ethoxybenzyl)-3-azopentane-1,5-diamine trihydrochloride of gadoxetate disodium, which belongs to Pharmaceutical and chemical industry. Background technique [0002] Magnetic resonance imaging (MRI) technology has been widely used in the fields of biology and medicine, and has become an important means of medical diagnosis. In order to enhance the contrast and clarity of images, it is necessary to select and use appropriate contrast agents in clinical MRI. At present, the important research direction of MRI contrast agents in the world is to develop contrast agents with organ and tissue targeting, so that the contrast agents can be enriched in specific organs or tissues, so as to improve the contrast effect and reduce the dosage and toxicity of drugs. [0003] Gadoxetic acid disodium (Gd-EOB-DTPA) is a liver-specific magnetic resonance contrast agent developed by Schering, Ge...

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Problems solved by technology

[0008] Chinese patent document CN101007775A discloses the preparation method of S-1-(4-ethoxybenzyl)-3-azopentane-1,5 diamine shown in the following route 1, the route uses amino-protected L-tyridine Amino acid ester as the starting material, after alkylation, ammonia substitution, deamination protection group, lithium aluminum tetrahydrogen (LiAlH 4 ) reduction to obtain S-1-(4-ethoxybenzyl)-3-azopentane-1,5-diamine, but this route uses iodoethane, a highly carcinogenic and highly toxic reagent, as an alkylating agent , has higher risk; and this method adopts expensive trifluoroacetic acid as reaction solvent and deprotection group reagent, and reaction consumption is big, and aftertreatment is difficult, causes environmental pollution easily; Moreover, this route uses the reaction condition requirement The reduction reaction of relatively high aluminum tetrahydrogen lithium requires anhydrous and oxygen-free, high safety requirements, high risk of operation and difficulty in post-processing, and the total yield is only 53%.

[0015] In addition, the document Inorg.Chem.1999,38,1134-1144 discloses the preparation of S-1-(4-ethoxybenzyl)-3-azopentane-1,5 diamine dihydrochloride shown in route 3 Preparation method, this route 3 also uses highly toxic reagent ethyl iodide and high-pressure catalytic hydrogenation in the process, which is harsh to the reaction conditions and has a large safety risk, which is not conducive to industrial production

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