Synthesis of coelenterazine

Patent metadata

Field	Value
Publication number	US-11078200-B2
Application number	US-202016851962-A
Country	US
Kind code	B2
Filing date	Apr 17, 2020
Priority date	Jun 29, 2018
Publication date	Aug 3, 2021
Grant date	Aug 3, 2021

Abstract

Disclosed herein are synthesis methods for coelenterazine. Also disclosed are articles including the coelenterazine and coelenterazine derivatives. Representative absorbent articles include disposable diapers and adult incontinence products.

First claim

The embodiments of the disclosure in which an exlusive property or privelage is claimed are defined as follows:

1. A method of making coelenterazine, comprising:
coupling 4-(5-amino-6-benzylpyrazin-2-yl)phenol (coelenteramine) with 3-(4-(benzyloxy)phenyl)-2-oxopropanal to provide 8-benzyl-2-(4-(benzyloxy)benzyl)-6-(4-hydroxyphenyl)imidazo[1,2-α]pyrazin-3(7H)-one; and
deprotecting the 8-benzyl-2-(4-(benzyloxy)benzyl)-6-(4-hydroxyphenyl)imidazo[1,2-α]pyrazin-3(7H)-one to provide 8-benzyl-2-(4-hydroxybenzyl) -6-(4-hydroxyphenyl)imidazo [1,2-α]pyrazin-3(7H)-one (coelenterazine).

2. The method of claim 1 , wherein coupling the 4-(5-amino-6-benzylpyrazin-2-yl)phenol (coelenteramine) with the 3-(4-(benzyloxy)phenyl)-2-oxopropanal is in a solvent mixture comprising dioxane, water, and HC1.

3. The method of claim 2 , wherein coupling the 4-(5-amino-6-benzylpyrazin-2-yl)phenol (coelenteramine) with the 3-(4-(benzyloxy)phenyl)-2-oxopropanal is at a temperature of 75° C. to 90° C. for 12 to 36 hours in an inert atmosphere.

4. The method of claim 1 , wherein deprotecting the 8-benzyl-2-(4-(benzyloxy)benzyl)-6-(4-hydroxyphenyl)imidazo[1,2-α]pyrazin-3(7H)-one comprises a first deprotection step of exposing the 8-benzyl-2-(4-(benzyloxy)benzyl)-6-(4-hydroxyphenyl)imidazo[1,2-α]pyrazin-3(7H)-one to HC1 in an organic solvent comprising dioxane, and isolating and drying an intermediate deprotected product.

5. The method of claim 4 , wherein the first deprotection step is at a temperature of 25° C. to 40 ° C.

6. The method of claim 4 , further comprises a second deprotection step of exposing the dried intermediate deprotected product to HC1 in an organic solvent comprising dioxane.

7. The method of claim 6 , wherein the second deprotection step comprises heating the intermediate deprotected product in HC1 and the organic solvent to a temperature of about 70° C. to 75° C. for a duration of 12 to 24 hours to provide coelenterazine.

8. The method of claim 1 , wherein the coelenterazine is obtained in a yield of greater than 70% at a purity of from 55% to 70% relative to 4-(5-amino-6-benzylpyrazin-2-yl)phenol.

9. The method of claim 1 , further comprising making the 3-(4-(benzyloxy)phenyl)-2-oxopropanal by reacting 1-(benzyloxy)-4-(chloromethyl)benzene in two steps to provide 3-(4-(benzyloxy)phenyl)-2-oxopropanal.

10. The method of claim 9 , wherein making the 3-(4-(benzyloxy)phenyl)-2-oxopropanal does not include more than one palladium-catalyzed reaction.

11. The method of claim 9 , comprising a first step of reacting the 1-(benzyloxy)-4-(chloromethyl)benzene with methyl 2,2-dimethoxyacetate, ethyl bromide, magnesium, and a catalytic amount of iodine to provide 3-(4-(benzyloxy)phenyl)-1,1-dimethoxypropan-2-one.

12. The method of claim 11 , wherein the 3-(4-(benzyloxy)phenyl)-1,1-dimethoxypropan-2-one is purified by silica column chromatography.

13. The method of claim 12 , further comprising a second step of reacting the 3-(4-(benzyloxy)phenyl)-1,1-dimethoxypropan-2-one with aqueous HC1 to provide the 3-(4-(benzyloxy)phenyl)-2-oxopropanal.

14. The method of claim 9 , wherein the 3-(4-(benzyloxy)phenyl)-2-oxopropanal is isolated in a yield of 60 to 75% at a purity of 85 to 95% relative to 1-(benzyloxy)-4-(chloromethyl)benzene.

Assignees

• Int Paper Co

Inventors

• Duvvuru Rajagopala Reddy

Classifications

• C07C49/00

  Ketones; Ketenes; Dimeric ketenes (heterocyclic compounds C07D, e.g. beta-lactones C07D305/12); Ketonic chelates · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07C45/455

  with carboxylic acids or their derivatives · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07C45/515

  the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group (cyclic acetals or ketals C07C45/59, C07C45/60) · CPC title