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Synthesis method of (S)-1-(4-ethyoxyl benzyl)-3-azapentane-1,5-diamine trihydrochloride

A technology of diamine trihydrochloride and ethoxybenzyl group is applied in the field of pharmaceutical chemical synthesis, which can solve the problems of non-production process, high environmental protection pressure and high equipment requirements, and achieves novel and concise steps, convenient post-processing, and mild reaction. Effect

Inactive Publication Date: 2014-06-18
FUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Method 3 (Inorg Chem, 1999, 38: 1134-1144) uses palladium carbon catalyzed hydrogenation deprotection group, high equipment requirements , safety is not easy to guarantee; the methanesulfonyl chloride used is highly toxic, and the pressure on environmental protection is relatively high; in addition, the synthesis steps are cumbersome
Overall, the process is not the best production process

Method used

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  • Synthesis method of (S)-1-(4-ethyoxyl benzyl)-3-azapentane-1,5-diamine trihydrochloride
  • Synthesis method of (S)-1-(4-ethyoxyl benzyl)-3-azapentane-1,5-diamine trihydrochloride
  • Synthesis method of (S)-1-(4-ethyoxyl benzyl)-3-azapentane-1,5-diamine trihydrochloride

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Experimental program
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Effect test

Embodiment 1

[0030] Take a 100 mL two-neck reaction flask, N 2 Add compound 1 sequentially under protection ( R )-2-(tert-butoxycarbonyl)amino)-3-(4-ethoxyphenyl)propanoic acid methyl ester 3.00 g (9.27 mmol), 20 mL of anhydrous toluene, placed in -40 ℃ cold trap Stir for later use; take another 100 mL cock reaction bottle, N 2 Add 70wt% red aluminum toluene solution (dihydrobis(2-methoxyethoxy)sodium aluminate 5.35 g (18.5 mmol)) under protection, then add morpholine (1.78 g , 20.4 mmol), continue to stir for 2 h after the dropwise addition; then slowly add the red aluminum solution dropwise to the first reaction flask, N 2 Under protection, react at -40 °C for 3 h. Add NaSO after the reaction is complete 4 10H 2 O (5.09 g, 18.5 mmol) was used to quench the reaction, then 20 mL of ethyl acetate was added to dilute, suction filtered and concentrated by rotary evaporation, and 1.39 g of white solid was obtained by column chromatography (petroleum ether: ethyl acetate = 10:1). Tha...

Embodiment 2

[0034] Take a 100 mL two-neck reaction flask, N 2 Add compound 1 sequentially under protection ( R )-2-(tert-butoxycarbonyl)amino)-3-(4-ethoxyphenyl)propionic acid methyl ester, 3.00 g (9.27 mmol), 20 mL of anhydrous toluene, placed in a -40 ℃ cold trap Stir for later use; take another 100 mL cock reaction bottle, N 2 Add 70% red aluminum toluene solution (sodium dihydrobis(2-methoxyethoxy)aluminate, 16.1 g, 55.5 mmol) under protection, and then add morpholine (5.34 g , 61.2 mmol), continue to stir for 2 h after the dropwise addition; then slowly add the red aluminum solution dropwise to the first reaction flask, N 2 Under protection, react at -40 °C for 3 h. Add NaSO after the reaction is complete 4 10H 2 O (15.3 g, 55.5 mmol) was used to quench the reaction, then 20 mL of ethyl acetate was added to dilute, suction filtered and concentrated by rotary evaporation, and 1.71 g of white solid was obtained by column chromatography (petroleum ether: ethyl acetate = 10:1). Na...

Embodiment 3

[0038] Take a 100 mL two-neck reaction flask, N 2 Add compound 1 sequentially under protection ( R )-2-(tert-butoxycarbonyl)amino)-3-(4-ethoxyphenyl)propionic acid methyl ester, 3.00 g (9.27 mmol), 20 mL of anhydrous toluene, placed in a -40 ℃ cold trap Stir for later use; take another 100 mL cock reaction bottle, N 2 Add 70% red aluminum toluene solution (sodium dihydrobis(2-methoxyethoxy)aluminate, 16.1 g, 55.5 mmol) under protection, and then add morpholine (5.34 g , 61.2 mmol), continue to stir for 2 h after the dropwise addition; then slowly add the red aluminum solution dropwise to the first reaction flask, N 2 Under protection, react at -55 °C for 2 h. Add NaSO after the reaction is complete 4 10H 2 O (15.3 g, 55.5 mmol) was used to quench the reaction, then 20 mL of ethyl acetate was added to dilute, suction filtered and concentrated by rotary evaporation, and 2.08 g of a white solid was obtained by column chromatography (petroleum ether: ethyl acetate = 10:1). ...

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Abstract

The invention provides a synthesis method of a gadoxetate disodium key precursor-(S-1-(4-ethyoxyl benzyl)-3-azapentane-1,5-diamine trihydrochloride. The synthesis method comprises the following steps: taking O-ethyl-N-Boc-L-tyrosine ethyl ester (a compound 1) as a material; reducing the material by red aluminum to obtain O)-ethyl-N-Boc-L-tyrosine aldehyde (a compound 2); then obtaining 1,5-Boc double-protection (S)-1-(4-ethyoxyl benzyl)-3-azapentane-1,5-diamine (a compound 3) by virtue of amination and reduction with N-Boc-1,2-ethanediamine under catalysis of sodium triacetoxyborohydride; finally, removing Boc protective groups through concentrated hydrochloric acid or a hydrogen chloride gas so as to obtain the (S)-1-(4-ethyoxyl benzyl)-3-azapentane-1,5-diamine trihydrochloride (a compound 4). According to the synthesis method disclosed by the invention, synthesis route steps are novel and concise, dear and dangerous special reagents are not needed, reaction is gentle, a product is easy to purify, after-treatment is convenient, and therefore, the synthetic method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to the key precursor of adult liver T1 magnetic resonance contrast agent gadoxetate disodium-( S )-1-(4-ethoxybenzyl)-3-azopentane-1,5-diamine trihydrochloride synthetic method. Background technique [0002] Gadoxetate disodium (gadoxetate disodium; trade name: Eovist), a gadolinium contrast agent, was developed by Bayer AG of Germany and was approved by the U.S. Food and Drug Administration (FDA) on July 3, 2008. An organ-specific MRI contrast agent approved in the United States, it is mainly used for adult liver T1 MRI to detect patients with confirmed or suspected liver diseases (Li Shanrong, Sun Tiemin, etc., Chinese Journal of Medicinal Chemistry, 2008, 18: 478). [0003] The synthetic method of this diagnostic reagent is as follows figure 1 Shown: by precursor—( S )-1-(4-ethoxybenzyl)-3-azopentane-1,5-diamine, which was replaced by 5 bromobutyl ...

Claims

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Application Information

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IPC IPC(8): C07C217/62C07C213/02
CPCY02P20/55
Inventor 唐凤翔宋小攀黄杨威赵学清
Owner FUZHOU UNIV
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