# US 2021/0276961 A1 · Method for manufacturing calcobutrol

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- Number: US 2021/0276961 A1
- Document ID: US20210276961A1
- Status: Published application
- Kind: A1
- Application number: 17/193,592
- Filed: 2021-03-05
- Published: 2021-09-09
- Earliest claimed: 2020-03-06
- Assignees: Enzychem Lifesciences Corporation
- Applicants: Enzychem Lifesciences Corporation
- Inventors: Jong Soo LEE; Dae Myoung YUN; Byuong Woo LEE
- Web page: https://patentgrep.com/patent/US20210276961A1

## CPC

- C07D 257/00: Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D 257/02: not condensed with other rings
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

It is disclosed a method for preparing calcobutrol, an excipient for preparing gadobutrol injections used as MRI contrast agents. the present invention provides a method for producing calcobutrol comprising: reacting lithium chloride and 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane with 1,4,7,10-tetraazacyclododecane represented by the following Formula 1 to obtain a calcobutrol intermediate represented by the following Formula 2; reacting the calcobutrol intermediate represented by Formula 2 with chloroacetic acid to obtain butrol represented by the following Formula 3; and reacting butrol represented by Formula 3 with calcium ion to obtain calcobutrol represented by Formula 4 below.

## Claims

### Claim 1

A method for producing calcobutrol comprising:
reacting lithium chloride and 4,4-dimethyl-3,5, 8-trioxabicyclo[5,1,0]octane with 1,4,7,10-tetraazacyclododecane represented by the following Formula 1 to obtain a calcobutrol intermediate represented by the following Formula 2;
reacting the calcobutrol intermediate represented by Formula 2 with chloroacetic acid to obtain butrol represented by the following Formula 3; and
reacting butrol represented by Formula 3 with calcium ion to obtain calcobutrol represented by Formula 4 below.

### Claim 2 (depends on 1)

The method of claim 1, wherein the pH is 8 to 12 when preparing the butrol.

### Claim 3 (depends on 1)

The method of claim 1, wherein the butrol is purified using nanofilter.

### Claim 4 (depends on 1)

The method of claim 1, wherein the calcium ion is selected from the group consisting of calcium carbonate, calcium hydroxide, calcium chloride, and mixtures thereof, and the content of calcium ion is 0.95 to 1.05 equivalents based on the butrol.

### Claim 5 (depends on 1)

The method of claim 1, wherein the amount of chloroacetic acid used is 3.0 to 4.5 equivalents based on the calcobutrol immediate.

### Claim 6 (depends on 1)

The method of claim 1, wherein the amount of 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane used is 1.0 to 1.5 equivalents based on the cyclen-lithium chloride complex.

### Claim 7 (depends on 1)

The method of claim 1, wherein it is crystallized using a crystallization solvent selected from the group consisting of methanol, ethanol, isopropanol, and acetone, in the step of obtaining calcobutrol.