Class of near infrared molecular probes for biological applications

Patent metadata

Field	Value
Publication number	US-9499528-B2
Application number	US-201414247812-A
Country	US
Kind code	B2
Filing date	Apr 8, 2014
Priority date	Apr 8, 2013
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

Methods for preparing 2,5-Bis(benzoxazol-2′-yl)benzene-1,4-diol derivatives (Zinhbo derivatives) are provided. Zinhbo derivatives are used to detect zinc ions and have particular application in vivo and in vitro. Zinhbo derivatives upon excitation give a florescence response emission that can be used to determine the presence of zinc cation in solution. Zinhbo derivatives complexed with zinc cations upon excitation can produce a florescence response emission in the visible and near infrared range. Zinhbo derivatives complexed with zinc cations exhibit a large stoke shift between the excitation and emission wavelengths.

First claim

What is claimed is:

1. A process of preparing a Zinhbo derivative comprising:
(i) reacting a protected compound defined by the formula:

where Y is an oxygen atom, a sulfur atom, a nitrogen atom with a pendant hydrogen atom, or a nitrogen atom with a pendant alkyl group; each Pr is individually a protecting group and R 1 , R 2 , R 3 , and R 4 are each individually selected from the group consisting of a hydrogen atom, an electron withdrawing group, and an electron donating group;
with a the 2-aminophenol derivative defined by the formula

where R 5 is a chelating group attached through a nitrogen atom, via a process that includes an oxidation reaction; and
(ii) deprotecting the protecting groups to form a Zinhbo derivation defined by the following formula:

where R 1 , R 2 , R 3 , and R 4 are each individually selected from the group consisting of a hydrogen atom, an electron withdrawing group, and an electron donating group; Y is an oxygen atom, a sulfur atom, a nitrogen atom with a pendant hydrogen atom, or a nitrogen atom with a pendant alkyl group; and R 5 is a chelating group attached through a nitrogen atom.

2. The method of claim 1 , where the 2-aminophenol is selected from

3. The method of claim 1 , where the protected compound is prepared by reacting a dihydroxybenzaldehyde with a hydroxymethyl group defined by:

where each Pr is individually a protecting group, with a an aminobenzene derivative defined by the formula:

where Y is an oxygen atom, a sulfur atom, a nitrogen atom with a pendant hydrogen atom, and R 1 , R 2 , R 3 , and R 4 are each individually selected from the group consisting of a hydrogen atom, an electron withdrawing group, and an electron donating group.

4. The method of claim 1 , where the 2-aminophenol derivative is prepared by
(i) reacting a nitrobenzene derivative defined by the formula

where Pr is a protecting group, and R 6 is a halogen atom or a tosyl group, with a amine compound that includes a chelating group;
(ii) deprotecting the protected oxygen atom; and
(iii) converting the nitro group to an amine.

5. The method of claim 1 , where the 2-aminophenol is prepared by
(i) reacting a nitrobenzene derivative defined by the formula

where X is a halogen, with a amine compound that includes a chelating group; and
(ii) converting the nitro group to an amine.

6. A process for preparing a Zinhbo derivative comprising:
(i) reacting a protected compound defined by the formula:

where Y is an oxygen atom, a sulfur atom, a nitrogen atom with a pendant hydrogen atom, or a nitrogen atom with a pendant alkyl group; each Pr is individually a protecting group and R 1 , R 2 , R 3 , and R 4 are each individually selected from the group consisting of a hydrogen atom, an electron withdrawing group, and an electron donating group, with a 2-aminophenol derivative defined by the formula

via a process that includes an oxidation reaction, to prepare a molecule defined by the formula I:

where each Pr is individually a protecting group, Y is an oxygen atom, a sulfur atom, a nitrogen atom with a pendant hydrogen atom, or a nitrogen atom with a pendant alkyl group, and R 1 , R 2 , R 3 , and R 4 are each individually selected from the group consisting of a hydrogen atom, an electron withdrawing group, and an electron donating group;
(ii) converting the OH group of formula I to a halogen atom or tosyl group;
(iii) reacting the halogen atom or tosyl group with a an amine compound that includes a chelating group;
(iv) deprotecting the protecting groups to form a Zinhdo derivative defined by the following formula:

where R 1 , R 2 , R 3 , and R 4 are each individually selected from the group consisting of a hydrogen atom, an electron withdrawing group, and an electron donating group; Y is an oxygen atom, a sulfur atom, a nitrogen atom with a pendant hydrogen atom, or a nitrogen atom with a pendant alkyl group; and R 5 is a chelating group attached through a nitrogen atom.

7. The method of claim 6 , where the amine compounds that includes a chelating group is selected from di-2-picolylamine, 1,4,7,10-tetrazacyclododecane, and pyridin-2-ylmethyl)amine.

8. The method of claim 6 , where formula 1 is produced by reacting the protected compound with the 2-aminophenol derivative in the presence of oxygen.

9. The method of claim 8 , were the protected compound and the 2-aminophenol derivative in the presence of oxygen in a solvent at 110 to 120° C. for about 2 to 4 hr.

10. A process for preparing a Zinhbo derivative comprising:
(i) reacting a protected compound defined by the formula:

where Y is an oxygen atom, a sulfur atom, a nitrogen atom with a pendant hydrogen atom, or a nitrogen atom with a pendant alkyl group; each Pr is individually a protecting group and R 1 , R 2 , R 3 , and R 4 are each individually selected from the group consisting of a hydrogen atom, an electron withdrawing group, and an electron donating group, with a 2-aminophenol derivative defined by the formula

where Pr is a protecting group, via a process that includes an oxidation reaction, to prepare a molecule defined by formula I:

where each Pr is individually a protecting group Y is an oxygen atom, a sulfur atom, a nitrogen atom with a pendent hydrogen atom, or a nitrogen atom with a pendant alkyl group, and R 1 , R 2 , R 3 , and R 4 are each individually selected from the group consisting of a hydrogen atom, an electron withdrawing group, and an electron donating group;
(ii) converging the CO 2 Pr group of formula I to a CH 2 OH group;
(iii) converting the OH group of the CH 2 OH group of step (ii) to a halogen atom or tosyl group;
(iv) reacting the halogen atom or tosyl group with an amine compound that includes a chelating group;
(v) deprotecting the protecting groups to form a Zinhbo derivative defined by the following formula:

where R 1 , R 2 , R 3 , and R 4 are each i

Assignees

• Pang Yi
• Wang Junfeng
• Univ Akron

Inventors

• Pang Yi
• Wang Junfeng

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title