Method for preparing gadobutrol
Inventors
BYEON, Changho • YOON, Hoejin • KIM, Moonsu • JEONG, Seongsu • PARK, Jongmoon • Lee, Junwon • WOO, Seokhun • Chang, Sun Ki
Assignees
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Publication Number
US-12180237-B2
Publication Date
2024-12-31
Expiration Date
Abstract
The present invention provides a novel method for preparing high-purity gadobutrol or hydrates thereof. The preparation method of the present invention can have an advantage of simplifying a process by forming a gadolinium complex in-situ without purification of a butrol intermediate and omitting a resin purification process unlike a conventional method for synthesizing gadobutrol. In addition, the preparation method of the present invention can be used to produce high-purity gadobutrol or hydrates thereof at a high yield only through the simple process as above, and thus can be useful in mass production.
Core Innovation
The invention relates to a method for preparing gadobutrol or hydrates thereof. The method includes a two-stage sequence in which a compound of formula 3, or a salt, is converted by carboxymethylation to a compound of formula 2 in a mixed solvent consisting of water and isopropyl alcohol.
In the second stage, the compound of formula 2 is subjected to basic hydrolysis, during which a gadolinium complex is formed in-situ to prepare a compound of formula 1. The formula 1 compound corresponds to gadobutrol or hydrates thereof as expressed by the method definitions in the patent.
The method is contrasted with conventional schemes that require resin purification of the butrol intermediate and that show disadvantages such as low yield and resin-intensive purification, together with insufficient purity relative to an ICH impurity threshold. The disclosed process emphasizes preparing gadobutrol with high-purity and high-yield characteristics by simplifying the synthesis sequence, including avoiding resin purification in S-2 in at least one independent claim.
Claims Coverage
The patent document provides two independent claims. Both independent claims cover the same overall inventive structure: carboxymethylation of a formula 3 compound to formula 2 followed by basic hydrolysis with in-situ gadolinium complex formation to obtain a formula 1 gadobutrol or hydrates, with the main differences being the mixed solvent for (S-1) and whether resin is used in (S-2).
Two-stage carboxymethylation to formula 2 followed by basic hydrolysis with in-situ gadolinium complex to formula 1
A method for preparing gadobutrol or hydrates thereof comprising (S-1) subjecting a compound of formula 3 or a salt to a carboxymethylation reaction to prepare a compound of formula 2; and (S-2) subjecting the compound of formula 2 to a basic hydrolysis and forming a gadolinium complex in-situ to prepare a compound of formula 1.
Mixed water/isopropyl alcohol solvent for carboxymethylation in (S-1)
In the method, said (S-1) is performed in a mixed solvent wherein the mixed solvent is a mixture of water and isopropyl alcohol.
No resin used in (S-2) while forming the in-situ gadolinium complex
In the method, said (S-2) does not use a resin.
Across the independent claims, the core claim coverage is the conversion of a formula 3 compound to a formula 2 compound by carboxymethylation, and the subsequent conversion of formula 2 to gadobutrol by basic hydrolysis with in-situ gadolinium complex formation, with one independent claim additionally requiring the mixed water/isopropyl alcohol solvent for (S-1) and the other independent claim explicitly excluding resin use in (S-2).
Stated Advantages
Provides a gadobutrol manufacturing approach aimed at high-purity and high-yield production by simplifying synthesis.
Avoids resin purification of the butrol intermediate, addressing resin-intensive purification of conventional schemes.
Achieves gadobutrol/monohydrate purity values up to about 99.97%–99.99% (as exemplified in the provided content) and targets compliance relative to an ICH impurity threshold (≤0.1%).
Documented Applications
Manufacturing/preparation of the gadolinium contrast agent gadobutrol (and hydrates) with high purity and high yield.
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