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

A technology of diamine trihydrochloride and ethoxybenzyl is applied in the preparation of amino hydroxy compounds, the preparation of organic compounds, chemical instruments and methods, etc. Difficulty in post-processing

Active Publication Date: 2014-07-02
QILU PHARMA HAINAN +1
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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 environm

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

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preparation example Construction

[0020] A preparation method of S-1-(4-ethoxybenzyl)-3-azopentane-1,5 diamine trihydrochloride, comprising the following steps:

[0021] (1) In the presence of inorganic bases and iodides, amino-protected L-tyrosine alkyl esters (SM1) react with ethyl bromide in reaction solvent I for 4-6 hours at room temperature, filter, and distill the filtrate to remove the solvent Obtain compound V;

[0022]

[0023] (2) React compound V and sodium borohydride in reaction solvent II at room temperature for 1~3h, distill off the solvent under reduced pressure, dissolve the residue in water, add ethyl acetate for extraction, separate the ethyl acetate phase, and distill out under reduced pressure Solvent obtains compound IV;

[0024]

[0025] (3) In the presence of fuacid, compound IV and alkylsulfonyl chloride (R 2 -SO 2 Cl) react in reaction solvent III at room temperature for 1.5~2.5h, filter to obtain a solution of compound III; add ethylenediamine to compound III filtrate, and ...

specific Embodiment approach

[0054] The above-mentioned content of the present invention will be further described in detail below through specific embodiments, but this should not be understood as any limitation on the protection subject matter of the present invention. All technical solutions realized based on the above content of the present invention belong to the scope of the present invention.

[0055] The present invention provides general and / or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of manipulation which are employed for the purposes of the invention are well known in the art, the invention has been described here in as much detail as possible. It is clear to those skilled in the art that in the following, if not specifically stated, the operation of the present invention is conventional or well known in the art; the test materials used can be prepared by conventional test methods by those skilled in the art through prior...

Embodiment 1

[0056] Example 1, Preparation of O-ethyl-N-tert-butoxycarbonyl-L-tyrosine methyl ester (compound V)

[0057] Dissolve 30kg (102mol) N-tert-butoxycarbonyl-L-tyrosine methyl ester in 150L N,N-dimethylformamide, add 44kg (404mol) bromoethane, 56kg (405mol) potassium carbonate and 1.35 kg (8.2mol) potassium iodide, reacted at 30°C for 5h, filtered, and evaporated the organic phase to obtain 32.7kg of compound V, yield 99.7%, HPLC purity 99.5%, MS[M+H] + :324.16, 1 H NMR (600MHz, CDCl 3 ):δ=7.02(d,J=8.4Hz,2H);6.83–6.80(m,2H);4.97(d,J=7.2Hz,1H);4.55-4.52(m,2H);4.00(dd, J=8.8,13.8Hz,2H);3.71(s,3H);3.06-2.98(m,2H);1.42(s,9H);1.40(t,J=4.8Hz;3H).

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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...

Claims

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Application Information

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IPC IPC(8): C07C217/62C07C213/00
CPCY02P20/55
Inventor 冷传新王玉兵刘培元范传文林栋张永晖齐宪亮
Owner QILU PHARMA HAINAN
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