Method for preparation of (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride
Inventors
Kim, Yeong Hun • BAEK, Hyun Woo • LEE, Hyeon Jin • Kang, Sang Kyu • Chang, Sun Ki • Lim, Geun Jho
Assignees
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Publication Number
US-10501403-B2
Publication Date
2019-12-10
Expiration Date
Abstract
The present invention relates to a novel method for preparing (S)—N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride.
Core Innovation
The invention relates to preparing (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride, identified as a key intermediate for manufacturing gadoxetate disodium (EOVIST®). The background problem is that prior routes require introducing the alkoxy group using hydroxy-containing precursors and additional hydrogenation steps, including Pd/C.
The solution streamlines the synthesis by starting from commercially available 1-halo-4-ethoxybenzene derivatives, where X is bromo or chloro and R is C1-6 alkyl. The sequence forms a Formula 2 intermediate via Grignard coupling of a compound of Formula 1, converts it to a Formula 3 azide via azide substitution with sodium azide, and then cyclizes the azide to an aziridine derivative using triphenylphosphine with amino protection.
The invention continues by ring opening the protected aziridine derivative to obtain a Formula 5 compound, followed by removing the amino-protecting group to produce the target trihydrochloride (Formula 6). The disclosed approach supports the use of the trihydrochloride as the key intermediate for gadoxetate disodium manufacture.
Claims Coverage
The provided independent claim describes one multi-step synthetic method for preparing (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride, with five core transformations and constraints on X and R.
Sequential synthesis from Formula 1 through Formula 6 intermediates
The method prepares (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride by preparing a Formula 2 compound via Grignard coupling of a Formula 1 compound, preparing a Formula 3 compound by azide substitution of the Formula 2 compound with sodium azide, preparing an aziridine derivative of Formula 4 having an amino group protected by an amino-protecting group by cyclization of the Formula 3 compound using triphenylphosphine, preparing a Formula 5 compound by ring opening of the Formula 4 compound, and preparing a Formula 6 compound by a reaction for removing the amino-protecting group of the Formula 5 compound.
Controlled starting halogen and alkoxy substituent definitions
In the method, X is bromo or chloro, and R is C1-6 alkyl.
The claim coverage centers on a defined conversion pathway from Formula 1 to Formula 6, ending in the target trihydrochloride, with the starting substituents constrained by X and R.
Stated Advantages
Streamlines synthesis of the key intermediate by avoiding prior routes that require introducing the alkoxy group through hydroxy-containing precursors and additional hydrogenation steps.
Enables preparation of the (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride as a key intermediate for manufacturing gadoxetate disodium (EOVIST®).
Documented Applications
The (S)-N1-(2-aminoethyl)-3-(4-alkoxyphenyl)propane-1,2-diamine trihydrochloride is described as a key intermediate for manufacture of gadoxetate disodium (EOVIST®).
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