# US 12,180,237 B2 · Method for preparing gadobutrol > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,180,237 B2 - Document ID: US12180237B2 - Status: Granted - Kind: B2 - Application number: 17/270,268 - Filed: 2019-08-23 - Published: 2021-10-14 - Granted: 2024-12-31 - Earliest claimed: 2018-08-23 - Assignees: St Pharm Co., Ltd. - Applicants: St Pharm Co., Ltd. - Inventors: Changho Byeon; Hoejin Yoon; Moonsu Kim; Seongsu Jeong; Jongmoon Park; Junwon Lee; Seokhun Woo; Sun Ki Chang - Web page: https://patentgrep.com/patent/US12180237B2 ## CPC - C07D 257/02: not condensed with other rings - C07F 5/003: {without C-Metal linkages} - C07B 2200/13: Crystalline forms, e.g. polymorphs - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22) - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) ## 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. ## Claims ### Claim 1 A method for preparing gadobutrol or hydrates thereof, the method comprising: (S-1) subjecting a compound of formula 3 below or a salt thereof to a carboxymethylation reaction to prepare a compound of formula 2 below; and (S-2) subjecting the compound of said formula 2 to a basic hydrolysis and forming a gadolinium complex in-situ to prepare a compound of formula 1 below: wherein, in above formula 2, R is C1-C4 linear or branched-chain alkyl, wherein said (S-1) is performed in a mixed solvent, wherein the mixed solvent is a mixture of water and isopropyl alcohol. ### Claim 2 (depends on 1) The method according to claim 1, wherein, in said (S-1), the compound of said formula 3 or the salt thereof and a compound of formula 4 below are reacted in the presence of a base: wherein, R is C1-C4 straight or branched-chain alkyl, and X is halogen, TsO− or MsO−. ### Claim 3 (depends on 1) The method according to claim 1, wherein the salt of the compound of said formula 3 in said (S-1) is 4 hydrochloride salt of formula 3-1 below: ### Claim 4 (depends on 1) The method according to claim 1, wherein the compound of said formula 2 in said (S-1) is a compound of formula 2-1 below: ### Claim 5 (depends on 2) The method according to claim 2, wherein the base is an inorganic base. ### Claim 6 (depends on 5) The method according to claim 5, wherein the inorganic base is potassium carbonate (K2CO3), sodium hydrogen carbonate (NaHCO3), potassium hydrogen carbonate (KHCO3), or a mixture thereof. ### Claim 7 (depends on 1) The method according to claim 1, wherein said (S-1) further comprises a crystallization process. ### Claim 8 (depends on 7) The method according to claim 7, wherein a solvent used in the crystallization is methylene chloride, C3-C12 ester, or a mixture thereof. ### Claim 9 (depends on 8) The method according to claim 8, wherein the mixture is a mixture of methylene chloride and ethyl acetate. ### Claim 10 (depends on 1) The method according to claim 1, wherein said (S-2) does not use a resin. ### Claim 11 (depends on 1) The method according to claim 1, wherein said (S-2) comprises a process of adjusting pH to acid after completion of a basic hydrolysis reaction. ### Claim 12 (depends on 11) The method according to claim 11, wherein the pH is 2 to 5. ### Claim 13 (depends on 1) The method according to claim 1, wherein said (S-2) is to add a gadolinium ion source. ### Claim 14 (depends on 13) The method according to claim 13, wherein the gadolinium ion source is gadolinium oxide, gadolinium acetate, or gadolinium chloride. ### Claim 15 (depends on 1) The method according to claim 1, wherein said (S-2) comprises a salt removal process. ### Claim 16 (depends on 15) The method according to claim 15, wherein the salt removal process is performed through a nano filter. ### Claim 17 (depends on 15) The method according to claim 15, wherein an electrical conductivity of filtrate is 500 μS/cm or less in the salt removal process. ### Claim 18 (depends on 15) The method according to claim 15, wherein the salt removal process is performed by using 200 to 300 mL of water per 1 g of crude gadobutrol prepared by a reaction for forming the gadolinium complex. ### Claim 19 (depends on 1) The method according to claim 1, wherein said (S-2) further comprises a crystallization process. ### Claim 20 (depends on 19) The method according to claim 19, wherein a solvent used in the crystallization is water, C1-C4 alcohol, or a mixed solvent thereof. ### Claim 21 (depends on 20) The method according to claim 20, wherein the solvent used in the crystallization is methanol or anhydrous ethanol. ### Claim 22 (depends on 1) The method according to claim 1, wherein said method further comprises (S-3) purifying crude gadobutrol with resin. ### Claim 23 (depends on 22) The method according to claim 22, wherein the resin comprises a cation exchange resin and an anion exchange resin. ### Claim 24 (depends on 23) The method according to claim 23, wherein a volume ratio of the cation exchange resin and the anion exchange resin is 1:1 to 1:3. ### Claim 25 (depends on 1) The method according to claim 1, wherein said (S-3) further comprises a crystallization process. ### Claim 26 (depends on 25) The method according to claim 25, wherein a solvent used in the crystallization is water, C1-C4 alcohol, or a mixed solvent thereof. ### Claim 27 (depends on 26) The method according to claim 26, wherein a solvent used in the crystallization is ethanol. ### Claim 28 A method for preparing gadobutrol or hydrates thereof, the method comprising: (S-1) subjecting a compound of formula 3 below or a salt thereof to a carboxymethylation reaction to prepare a compound of formula 2 below; and (S-2) subjecting the compound of said formula 2 to a basic hydrolysis and forming a gadolinium complex in-situ to prepare a compound of formula 1 below: wherein, in above formula 2, R is C1-C4 linear or branched-chain alkyl, wherein said (S-2) does not use a resin. ### Claim 29 (depends on 28) The method according to claim 28, wherein said (S-2) comprises a salt removal process. ### Claim 30 (depends on 29) The method according to claim 29, wherein the salt removal process is performed through a nano filter.