CN102432614A - Method for synthesizing coelenterazine - Google Patents
Method for synthesizing coelenterazine Download PDFInfo
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- CN102432614A CN102432614A CN2011103625843A CN201110362584A CN102432614A CN 102432614 A CN102432614 A CN 102432614A CN 2011103625843 A CN2011103625843 A CN 2011103625843A CN 201110362584 A CN201110362584 A CN 201110362584A CN 102432614 A CN102432614 A CN 102432614A
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- coelenterazine
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- FMQSBWROAZZLPM-UHFFFAOYSA-N COc(cc1)ccc1-c(nc1Cc2ccccc2)cnc1N Chemical compound COc(cc1)ccc1-c(nc1Cc2ccccc2)cnc1N FMQSBWROAZZLPM-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a method for synthesizing coelenterazine. The method comprises the following steps of: 1) performing condensation and ring closing on a compound A and a compound B which are taken as raw materials in the presence of pyridine and TiCl4 so as to obtain a compound C; 2) deoxidizing the compound C through hydrogenation reduction to obtain a compound D; 3) demethylating the compound D and pyridine hydrochloride at the temperature of 200 DEG C to obtain a compound E; and 4) performing condensation and ring closing on the compound E and p-hydroxyphenylpyruvic acid to obtain a product G, namely the coelenterazine. The invention has the advantages that: an optimized method for synthesizing the coelenterazine is provided, and the coelenterazine is synthesized through four-step reaction according to a simple and convenient route; and raw materials used in the method are cheap and readily available, the cost is low, experimental steps are simple, the yield of various steps is high, and the method is suitable for industrialized scale-up production.
Description
Technical field
The present invention relates to a kind of compound method of coelenterazine, belong to the biological chemistry synthesis technical field.
Background technology
Coelenterazine (coelenterazine) is a kind of luciferin, can be luminous, and be the substrate of many luciferases and photoprotein, extensively be present in the aquatic organism, in the noclilucence system, occupy important status.Luciferin and luciferase or photoprotein combination are used to study adjusting and the expression of gene in multiple organism always.
Existing coelenterazine technology synthesis step is tediously long, troublesome poeration, and yield is low, and cost is higher, and it is synthetic and be not suitable for suitability for industrialized production to be only applicable to the laboratory.In view of the huge purposes of coelenterazine and the increase day by day of demand, present market supply simultaneously can not satisfy the demands far away, and therefore, seeking the coelenterazine synthetic route of optimizing just becomes the task of top priority.
Summary of the invention
The objective of the invention is to overcome the weak point of prior art, a kind of compound method of simple and easy to do coelenterazine is provided.
The compound method of coelenterazine of the present invention comprises the following steps:
1) be raw material with compd A and compd B, at pyridine and TiCl
4Ring is closed in following condensation, obtains Compound C, reaction process as shown in the formula:
2) Compound C obtains Compound D through the hydro-reduction deoxidation, reaction process as shown in the formula:
3) Compound D and pyridine hydrochloride obtain compd E at 200 ℃ of following demethylations, reaction process as shown in the formula:
4) compd E and the phenylor pyruvic acid closed ring through condensation obtains product G, i.e. coelenterazine, reaction process as shown in the formula.
The present invention has following technique effect: the invention provides the method for the synthetic coelenterazine of optimization, through four-step reaction, easier route has synthesized coelenterazine; The invention discloses a kind of coelenterazine synthetic method of comparatively optimizing; The present invention is raw materials used cheap and easy to get, and cost is lower, and experimental procedure is simple to operate; And the yield of each step is higher, is suitable for industrial amplification production.
Embodiment
Below in conjunction with embodiment the present invention is further described, but should not limit protection scope of the present invention with this.
Synthesizing of embodiment 1 Compound C
With compd A (90g, 0.493mol) and compd B (9.7g 0.493mol), is dissolved in the pyridine (700mL), stirs down 30min in-10 degree, slowly drips TiCl
4(214 grams 1.13mol) in reaction flask, dropwise, continue to stir 1 hour, and to room temperature, restir 2 hours.Then, reaction solution is poured in the frozen water, and adding Hydrogen chloride, to regulate pH value be about 4, use ethyl acetate extraction, and drying is revolved driedly, must restrain yield 86% by yellow solid 130.Product can directly be put in next step reaction.
Synthesizing of embodiment 2 Compound D
With Compound C (130 grams 0.423mol) are dissolved in the methyl alcohol (1500mL), add Raney Ni (15 gram), under the atmosphere of hydrogen, stir 15 hours, and reaction finishes, suction filtration, gained filtrating is revolved dried, Compound D (115 restrain), yield 93%.
Synthesizing of embodiment 3 compd Es
With Compound D (14g, 0.0481mol) and pyridine hydrochloride (56g 0.484mol) puts into the flask of 250 mL, stirs, and nitrogen protection is in 200
oC reacted 1 hour down.Reaction finishes, pours in the frozen water, and with the EA extraction, drying, column chromatography gets compd E (10 gram), yield 75%.
Embodiment 4 compound G's (coelenterazine) is synthetic
(10 grams, 0.036mol) and to the phenylor pyruvic acid (16.2 grams 0.09mol) are dissolved in the methyl alcohol, in 100 compd E
oMethyl alcohol is revolved in C heated and stirred reaction one hour then, and miscellany is in 150
oC reacted one hour down, and reaction finishes, and the miscellany column chromatography gets compound G (coelenterazine) (9.1 grams, yield 60%).
Claims (1)
1. the compound method of coelenterazine is characterized in that, comprises the following steps:
1) be raw material with compd A and compd B, at pyridine and TiCl
4Ring is closed in following condensation, obtains Compound C, reaction process as shown in the formula:
2) Compound C obtains Compound D through the hydro-reduction deoxidation, reaction process as shown in the formula:
3) Compound D and pyridine hydrochloride obtain compd E at 200 ℃ of following demethylations, reaction process as shown in the formula:
4) compd E and the phenylor pyruvic acid closed ring through condensation obtains product G, i.e. coelenterazine, reaction process as shown in the formula.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103625843A CN102432614A (en) | 2011-11-16 | 2011-11-16 | Method for synthesizing coelenterazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103625843A CN102432614A (en) | 2011-11-16 | 2011-11-16 | Method for synthesizing coelenterazine |
Publications (1)
| Publication Number | Publication Date |
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| CN102432614A true CN102432614A (en) | 2012-05-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011103625843A Pending CN102432614A (en) | 2011-11-16 | 2011-11-16 | Method for synthesizing coelenterazine |
Country Status (1)
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020061826A1 (en) * | 2018-09-26 | 2020-04-02 | 深圳华大智造极创科技有限公司 | Intermediate of coelenterazine compound and method for synthesizing coelenterazine compound |
| US11008326B2 (en) | 2018-06-29 | 2021-05-18 | International Paper Company | Synthesis of coelenterazine |
| US11078200B2 (en) | 2018-06-29 | 2021-08-03 | International Paper Company | Synthesis of coelenterazine |
| CN113264889A (en) * | 2021-06-11 | 2021-08-17 | 广西师范大学 | Method suitable for industrial production and preparation of gefitinib |
| US11505787B2 (en) | 2014-10-16 | 2022-11-22 | International Paper Company | Chemiluminescent wetness indicator for absorbent products |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997043267A1 (en) * | 1996-05-11 | 1997-11-20 | Kings College London | Pyrazines |
| WO2001087853A1 (en) * | 2000-05-17 | 2001-11-22 | Universite Catholique De Louvain | Aryl-substituted n,n-heterocyclic compounds, method for their preparation and their use in therapeutics and diagnostics |
| WO2010090318A1 (en) * | 2009-02-09 | 2010-08-12 | チッソ株式会社 | Coelenteramide analogs |
| CN101889095A (en) * | 2007-10-29 | 2010-11-17 | 珀金埃尔默健康科学有限公司 | Methods, reagents and kits for luciferase assay |
-
2011
- 2011-11-16 CN CN2011103625843A patent/CN102432614A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997043267A1 (en) * | 1996-05-11 | 1997-11-20 | Kings College London | Pyrazines |
| WO2001087853A1 (en) * | 2000-05-17 | 2001-11-22 | Universite Catholique De Louvain | Aryl-substituted n,n-heterocyclic compounds, method for their preparation and their use in therapeutics and diagnostics |
| CN101889095A (en) * | 2007-10-29 | 2010-11-17 | 珀金埃尔默健康科学有限公司 | Methods, reagents and kits for luciferase assay |
| WO2010090318A1 (en) * | 2009-02-09 | 2010-08-12 | チッソ株式会社 | Coelenteramide analogs |
Non-Patent Citations (4)
| Title |
|---|
| HISAE KAKOI，等: "IMPROVED SYNTHESIS OF WATASENIA PRELUCIFERIN", 《HEIEROCYCLES》 * |
| HISAE KAKOI: "Synthesis of 2-Amino-3-benzyl-5-(p-hydroxyphenyl)pyrazine", 《CHEM. PHARM. BULL.》 * |
| MARTINE KEENAN，等: "Highly efficient and flexible total synthesis of coelenterazine", 《CHEM. COMMUN.》 * |
| MASAKI KUSE，等: "Novel synthetic route of aryl-aminopyrazine", 《TETRAHEDRON》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11505787B2 (en) | 2014-10-16 | 2022-11-22 | International Paper Company | Chemiluminescent wetness indicator for absorbent products |
| US11008326B2 (en) | 2018-06-29 | 2021-05-18 | International Paper Company | Synthesis of coelenterazine |
| US11078200B2 (en) | 2018-06-29 | 2021-08-03 | International Paper Company | Synthesis of coelenterazine |
| US11926624B2 (en) | 2018-06-29 | 2024-03-12 | International Paper Company | Synthesis of coelenterazine synthesis intermediate |
| US11939332B2 (en) | 2018-06-29 | 2024-03-26 | International Paper Company | Synthesis of coelenterazine |
| WO2020061826A1 (en) * | 2018-09-26 | 2020-04-02 | 深圳华大智造极创科技有限公司 | Intermediate of coelenterazine compound and method for synthesizing coelenterazine compound |
| CN113264889A (en) * | 2021-06-11 | 2021-08-17 | 广西师范大学 | Method suitable for industrial production and preparation of gefitinib |
| CN113264889B (en) * | 2021-06-11 | 2023-08-08 | 广西师范大学 | Method suitable for industrial production and preparation of gefitinib |
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Application publication date: 20120502 |