# US 11,078,200 B2 · Synthesis of coelenterazine

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- Number: US 11,078,200 B2
- Document ID: US11078200B2
- Status: Granted
- Kind: B2
- Application number: 16/851,962
- Filed: 2020-04-17
- Published: 2020-07-30
- Granted: 2021-08-03
- Earliest claimed: 2018-06-29
- Assignees: International Paper Company
- Applicants: International Paper Company
- Inventors: Rajagopala Reddy Duvvuru
- Web page: https://patentgrep.com/patent/US11078200B2

## CPC

- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07C 45/455: {with carboxylic acids or their derivatives}
- C07C 45/515: {the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group (cyclic acetals or ketals C07C45/59, C07C45/60)}
- C07C 49/00: Ketones; Ketenes; Dimeric ketenes (heterocyclic compounds C07D, e.g. beta-lactones C07D305/12); Ketonic chelates
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## 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.

## Claims

### Claim 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).

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 2)

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.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 4)

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

### Claim 6 (depends on 4)

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.

### Claim 7 (depends on 6)

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.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 9)

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

### Claim 11 (depends on 9)

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.

### Claim 12 (depends on 11)

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

### Claim 13 (depends on 12)

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.

### Claim 14 (depends on 9)

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.