# US 2013/0156701 A1 · Method of preparing ethacrynic amide derivatives and application thereof

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- Number: US 2013/0156701 A1
- Document ID: US20130156701A1
- Status: Published application
- Kind: A1
- Application number: 13/715,513
- Filed: 2012-12-14
- Published: 2013-06-20
- Earliest claimed: 2011-12-15
- Assignees: National Tsing Hua University
- Inventors: CHUNG SHAN YU; CHUN NAN YEH; JENN-TZONG CHEN; WUU-JYH LIN; YIN-CHENG HUANG; LI-WU CHIANG; HAO LIEN HUANG; KANG-WEI CHANG; GON-SHEN CHEN; KEN-HONG LIN; WEI-TING WANG
- Web page: https://patentgrep.com/patent/US20130156701A1

## CPC

- C07C 231/12: by reactions not involving the formation of carboxamide groups
- A61K 51/04: Organic compounds
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- C07B 59/001: {Acyclic or carbocyclic compounds}
- C07C 269/02: from isocyanates with formation of carbamate groups
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- 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 method for preparing [18F]—N-(4-fluorobutyl)ethacrynic amide which is prepared from radiofluorination and deprotection of the precursor tosylate N-Boc-N-[4-(toluenesulfonyloxy)-butyl)ethacrynic amide], obtained from ethacrynic acid via 6-step synthesis in 39% yield, in a radiochemical yield of 44%, aspecific activity of 48 GBq/μmol and radiochemical purity of 98%. The present invention further provides a composition for positron emission tomography (PET) of an animal models of a tumor liver or a liver disease, comprising [18F]—N-(4-fluorobutyl)ethacrynic amide and a pharmaceutically acceptable carrier.

## Claims

### Claim 1

A method for preparing the compound of formula 1:
comprising: (a) reacting the compound of formula 2
with a 18F-labeled fluorine reagent and acetonitrile to form the compound of formula 3; and
(b) using the compound of formula 3 with trifluoro acetic acid and haloalkanes to form the compound of formula 1, wherein R1 is a protecting group of amide functional group and R2 is a leaving group.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the protecting group of amide functional group is tert-butoxycarbonyl; and the leaving group is tosyloxy, methanesulfonyl, trifluoromethanesulfonyloxyl or bromine;

### Claim 3 (depends on 1)

The method according to claim 1, wherein the 18F-labeled fluorine reagent is 18F-labeled tetrabutyl ammonium fluoride.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the compound of formula 2 is formed by reacting the compound of formula 4
with toluenesulfonyl chloride and a pyridine compound, wherein Boc is tert-butoxycarbonyl.

### Claim 5 (depends on 4)

The method according to claim 4, wherein the pyridine compound is 4-(dimethylamino)pyridine.

### Claim 6 (depends on 4)

The method according to claim 4, wherein the compound of formula 4 is formed by reacting the compound of formula 5
with tetrabutyl ammonium fluoride and acetic acid, wherein Boc is tert-butoxycarbonyl; OTBDMS is tert-butdimethoxysilane.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the compound of formula 5 is formed by reacting the compound of formula 6
and di-tert-butyl dicarbonate, wherein OTBDMS is tert-butdimethoxysilane.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the compound of formula 6 is formed by reacting ethacrynic acid with N-Boc-N-[4-(t-butyldimethylsilanyloxy)-butyl-1-amine.

### Claim 9 (depends on 1)

A composition for positron emission tomography (PET) imaging, comprising the compound of formula 1 according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 9)

The composition according to claim 9, wherein the positron emission tomography (PET) imaging is used in an animal model of a liver tumor or a liver disease.

### Claim 11 (depends on 10)

The composition according to claim 10, wherein the liver disease is cirrhosis.