CN102838553A - Synthesis method for electron carrier 1-methoxyl-5-methyl phenazine methosulfate - Google Patents
Synthesis method for electron carrier 1-methoxyl-5-methyl phenazine methosulfate Download PDFInfo
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- CN102838553A CN102838553A CN2012103587545A CN201210358754A CN102838553A CN 102838553 A CN102838553 A CN 102838553A CN 2012103587545 A CN2012103587545 A CN 2012103587545A CN 201210358754 A CN201210358754 A CN 201210358754A CN 102838553 A CN102838553 A CN 102838553A
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Abstract
The invention discloses a synthesis method for electron carrier 1-methoxyl-5-methyl phenazine methosulfate (1-methoxyl PMS), belonging to the technical field of chemical synthesis. According to the synthesis method, o-vanillin which is cheap and readily available on the market is used as a raw material, iodosobenzene diacetate is used as an oxidant, and four-step reaction is performed to obtain the 1-methoxyl PMS. The use of lead dioxide with high toxicity, expensive tetrachloro-o-benzoquinone, iodosobenzene with instable character is avoided. The method has the advantages of short line, safety, easiness in operation, total yield of reaching 26.3 percent of the four-step reaction, low cost and contribution to industrial production.
Description
Technical field
The invention belongs to chemosynthesis technical field, relate to the compound method of a kind of electron carrier 1-methoxyl group PMS.
Background technology
1-methoxyl group PMS, promptly 1-methoxyl group-5-toluphenazine methyl sulfate salt is a kind of electron carrier of using in the cytoactive detection reagent CCK-8 test kit.The CCK-8 test kit be the exploitation of Japanese Dojindo institute be used to detect cell proliferation, Cytotoxic test kit.This test kit is easy to use, highly sensitive, good reproducibility, "dead".1-methoxyl group PMS is as the electron carrier in its ingredient, have that susceptibility is good, stable in properties, be easy to advantages such as prolonged preservation, but commercially available price is high.What report was arranged at present mainly contains following several kinds with its synthetic relevant compound method:
1, be raw material with 3-methoxyl group pyrocatechol, CH
2Cl
2/ H
2O makes solvent, and through the PhIO oxidation, column chromatography gets the adjacent benzoquinones of 3-methoxyl group under the normal temperature.Yield 95% (
J. Org. Chem. 1983, 48,4764-4766).
2, be raw material with 3-methoxyl group pyrocatechol, benzene is made solvent, under the normal temperature through PbO
2Oxidation gets the adjacent benzoquinones of 3-methoxyl group.Without separation, normal temperature down with benzole soln reaction through the O-Phenylene Diamine of Glacial acetic acid min. 99.5 acidifying, Al is washed in alkali cleaning
2O
3Decolouring, recrystallization obtains 1-methoxyl group azophenlyene.Yield 33% (
Organic Syntheses, CV 3,753).
3, be raw material with 3-methoxyl group pyrocatechol, ether is made solvent, under-78 ℃ of conditions, gets the adjacent benzoquinones of 3-methoxyl group through the oxidation of monoethyl quinone.Without separation, normal temperature reacts with benzole soln through the O-Phenylene Diamine of Glacial acetic acid min. 99.5 acidifying down, and column chromatography obtains 1-methoxyl group azophenlyene.Yield 42% (
J. Med. Chem.
2010, 53,8688-8699).
4, be raw material with 5-chloro-2-Nitroanisole and aniline,, react under-60 ℃ of conditions, generate 2-methoxyl group-4-chloro-6-anilino nitrosobenzene at t-BuOK/ DMF.In BSA/ DMF, cyclization under the normal temperature condition obtains 3-chloro-1-methoxyl group azophenlyene then.After Pd (10%)/C hydrodechlorination obtains 1-methoxyl group azophenlyene.Total recovery 60% (
Tetrahedron Letters,
2011, 52,6484-6488).
Sum up above-mentioned several method, be not difficult to find, not enough below they exist: (1) starting raw material is 3-methoxyl group pyrocatechol or 5-chloro-2-Nitroanisole, and all price is higher; (2) oxygenant used of the adjacent benzoquinones of synthetic 3-methoxyl group has plumbic oxide, monoethyl quinone, iodosobenzene etc., these oxygenants exist toxicity big, cost an arm and a leg, shortcoming such as character instability, be not suitable for mass production; When (3) coupling generated 1-methoxyl group azophenlyene, the solvent of using was benzene mostly, and toxicity is big; (4) productive rate is low; (5) though method 4 productive rates are better relatively, severe reaction conditions, and dechlorination need Pd (10%)/C hydrogenation, cost is higher.
Summary of the invention
The object of the invention is to provide that a kind of cost is low, environment-protecting asepsis, be fit to the new synthetic method of the 1-methoxyl group PMS of suitability for industrialized production.
For realizing the object of the invention, the present invention is raw material with the o-vanillin, and the acetic acid iodobenzene is that oxygenant prepares 1-methoxyl group PMS.
The preparation method of 1-methoxyl group PMS provided by the invention is as follows:
The technical scheme that the present invention adopted is expressed as follows:
(1) makes solvent with aqueous sodium hydroxide solution, compound
1Through the hydrogen peroxide oxidation, extraction, column chromatography gets compound
2
(2) with methylene dichloride, ETHYLE ACETATE, toluene or chloroform give solvent, compound
2Through the oxidation of acetic acid iodobenzene, obtain compound
3
(3) compound
3In containing the methylene dichloride of acetic acid, ETHYLE ACETATE, toluene or chloroformic solution, with the O-Phenylene Diamine coupling, through washing, drying, the evaporate to dryness column chromatography obtains compound
4
(4) compound
4With the methyl-sulfate reaction, obtain compound
5
Specifically realize as follows:
The temperature of reaction of reaction is at 40 ~ 45 ℃ in the step (1); Reaction solvent is a 1mol/L NaOH solution; The oxygenant of reaction is mass percent 3% hydrogen peroxide; Hydrogen peroxide need slowly join in the reaction system, and molar ratio is a compound
1: NaOH:H
2O
2=1:1 ~ 2:1 ~ 1.5.
The temperature of reaction of reaction is at-78 ~ 50 ℃ in the step (2); The preferred methylene dichloride of reaction solvent; The acetic acid iodobenzene slowly joins in the reaction system, and molar ratio is a compound
1: acetic acid iodobenzene=1 ~ 3:2.
Temperature of reaction is at-78 ~ 50 ℃ in the step (3); The preferred methylene dichloride of reaction solvent; Molar ratio is a compound
1: acetic acid: O-Phenylene Diamine=1 ~ 2:1 ~ 4:1.
The temperature of reaction of reaction is at 100 ~ 120 ℃ in the step (4); Reaction 10min; Be cooled to 70 ~ 80 ℃ then, add ETHYLE ACETATE, slowly be chilled to normal temperature; Feed ratio is a compound
4: methyl-sulfate: ETHYLE ACETATE=2mmol: 1 ~ 3ml:20 ~ 50ml.
The present invention has following advantage:
1, use o-vanillin to be raw material, cheap and easy to get, reduced cost;
2, use the acetic acid iodobenzene to make oxygenant first, cheap, safety and stability has been avoided the iodosobenzene of the bigger plumbic oxide of use toxicity, expensive monoethyl quinone, proterties less stable etc.;
3, agents useful for same toxicity is less, has avoided using the bigger reagent of toxicity such as benzene to make reaction solvent;
4, easy and simple to handle, be easy to aftertreatment, be total to four-step reaction, total recovery reaches 26.3%.
Embodiment
To help to understand the present invention through following instance, but following instance only is used for preferred implementation of the present invention is described more specifically, is not used in qualification technical scheme of the present invention.The technical scheme of the invention described above is the technical scheme that can realize the object of the invention.Temperature and reagent that promptly following instance adopted, all available relevant temperature mentioned above and reagent substitute.
Embodiment 1
1, compound
2Preparation
Get compound
1(4.0g, 0.0263mol) in a 150ml there-necked flask, (30ml, 0.03mol) solution are stirred to dissolving fully to add 1mol/L NaOH.With 1/2 seconds speed, add mass percent 3%H
2O
2(30ml, 0.0386mol).In the dropping process, oil bath temperature is risen to 40 ℃.After dropwising, continue constant temperature and stir 10min.TLC detection reaction terminal point (PE/ EA=1).Be chilled to room temperature.Add the 2ml concentrated hydrochloric acid and transfer to acidity.Dichloromethane extraction (100ml * 4).Merge organic phase, anhydrous sodium sulfate drying.Filter.Evaporate to dryness, column chromatography revolves evaporate to dryness, gets compound
2(3.566g, 0.0255mol).Yield 96.8%.
1H-NMR(400MHz,?CDCl
3)?δ
H:?3.85(?s,?3H),?6.16(?s,?2H),?6.52(?dd,?1H,?
J=?8Hz,?1Hz),?6.69(?dd,?1H,?
J?=?8Hz,?1Hz?),?6.80(?t,?1H);?
13C-NMR(?400MHz,?CDCl
3)?δ
C:?56.2,?103.6,?109.1,?119.9,?132.6,?144.1,?147.3。
2, compound
3Preparation
Get compound
2(3.566g 0.0255mol) in a 250ml single port bottle, adds 40ml CH
2Cl
2Dissolving.Under the room temperature, slowly drip acetic acid iodobenzene (7.86g, dichloromethane solution 80ml 0.0244mol) (2/1 second).Dropwise, stir 10min, TLC detection reaction terminal point (PE/ EA=1).Without separation, directly drop into next step reaction.
3, compound
4Preparation
(2.6g 0.0241mol) in a 250ml single port bottle, adds 50ml CH to get O-Phenylene Diamine
2Cl
2And Glacial acetic acid min. 99.5 (2.5ml 0.0437mol), is stirred to whole dissolvings.Under the room temperature, slowly add the reaction solution in a last step, stir 1h, TLC detection reaction terminal point (PE/ EA=1).Distillation washing (50ml * 2), anhydrous sodium sulfate drying filters evaporate to dryness, column chromatography.Get compound
4(2.091g, 0.01mol), yield 41.3%.
1H-NMR(?400MHz,?CDCl
3)?δ
H:?4.19(?s,?3H),?7.09(?d,?1H,?
J?=?7Hz),?7.77(?m,?1H),?7.85(?m,?3H),?8.24(?m,?1H),?8.41(?m,?1H);?
13C-NMR(?400MHz,?CDCl
3)?δ
C:?56.5,?106.4,?121.4,?129.3,?130.21,?130.24,?130.5,?130.8,?136.8,?142.2,?143.5,?144.2,?155.1。
4, compound
5Preparation
Get compound
4(401mg 1.909mmol), adds 2ml Me
2SO
4, oil bath is stirred 10min for 100 ℃.Be cooled to about 70 ℃, add 40ml ETHYLE ACETATE, stir and continue to be cooled to room temperature.Ultrasonic 2min ,-20 ℃ of cooling 10min.Suction filtration to filtrating clarification repeatedly gets compound
5(469mg, 1.394mmol), yield 73.0%.
1H-NMR(?400MHz,?d
6-?DMSO)?δ
H:?4.07(?s,?3H),?7.27(?d,?1H,?
J?=?7Hz?),?7.77(?dd,?1H,?
J?=?8Hz,?0.8Hz?),?7.86(?t,?1H),?7.95(?m,?2H),?8.26(?m,?2H),?8.57(?s,?3H);?
13C-NMR(?400MHz,?d
6-?DMSO)?δ
C:?56.5,?107.8,?120.8,?129.3,?130.1,?131.08,?131.80,?131.88,?136.7,?141.9,?143.0,?143.8,?155.4。
Claims (7)
1. the compound method of an electron carrier 1-methoxyl group PMS is characterized in that, this method realizes through the following step:
(1) makes solvent with aqueous sodium hydroxide solution, compound
1Through the hydrogen peroxide oxidation, extraction, column chromatography gets compound
2
(2) with methylene dichloride, ETHYLE ACETATE, toluene or chloroform give solvent, compound
2Through the oxidation of acetic acid iodobenzene, obtain compound
3
(3) compound
3In containing the methylene dichloride of acetic acid, ETHYLE ACETATE, toluene or chloroformic solution, with the O-Phenylene Diamine coupling, through washing, drying, the evaporate to dryness column chromatography obtains compound
4
(4) compound
4With the methyl-sulfate reaction, obtain compound
5
2. the compound method of 1-methoxyl group PMS according to claim 1 is characterized in that, the temperature of reaction of step (1) reaction is at 40 ~ 45 ℃; The reaction raw materials mol ratio is a compound
1: NaOH:H
2O
2=1:1 ~ 2:1 ~ 1.5.
3. the compound method of 1-methoxyl group PMS according to claim 1 is characterized in that, step (2) temperature of reaction is controlled at-78 ~ 50 ℃; The preferred methylene dichloride of reaction solvent.
4. the compound method of 1-methoxyl group PMS according to claim 1 is characterized in that, in the step (2), the acetic acid iodobenzene slowly joins in the reaction system, and molar ratio is a compound
1: acetic acid iodobenzene=1 ~ 3:2.
5. the compound method of 1-methoxyl group PMS according to claim 1 is characterized in that, the preferred methylene dichloride of reaction solvent in the step (3); Temperature of reaction is controlled at-78 ~ 50 ℃.
6. the compound method of 1-methoxyl group PMS according to claim 1 is characterized in that, molar ratio is a compound in the step (3)
1: acetic acid: O-Phenylene Diamine=1 ~ 2:1 ~ 4:1.
7. the compound method of 1-methoxyl group PMS according to claim 1 is characterized in that, the temperature of reaction of step (4) is 100 ~ 120 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974099A (en) * | 2015-07-23 | 2015-10-14 | 西安瑞联近代电子材料有限责任公司 | New synthesis method of phenazine |
| CN106699722A (en) * | 2016-12-26 | 2017-05-24 | 上海生农生化制品股份有限公司 | Synthetic method of 2,2-dichloro-1,3-benzodioxole-4-formaldehyde |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5639196B2 (en) * | 1977-05-12 | 1981-09-11 |
-
2012
- 2012-09-25 CN CN2012103587545A patent/CN102838553A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5639196B2 (en) * | 1977-05-12 | 1981-09-11 |
Non-Patent Citations (8)
| Title |
|---|
| ALEXANDER R. SURREY: "PYOCYANINE", 《ORGANIC SYNTHESES COLLECTION》 * |
| ANDREW PELTER ET AL.: "Phenolic oxidation with (diacetoxyiodo)benzene", 《TETRAHEDRON LETTERS》 * |
| CHEN, SHUAI ET AL: "Organocatalytic Dakin Oxidation by Nucleophilic Flavin Catalysts", 《ORGANIC LETTERS》 * |
| KATO N，ET AL.: "Facile and Efficient Synthesis of 7, 10-Dihydroxy-6H-pyrazolo [4, 5, 1-de] acridin-6-one via Hypervalent Iodine Oxidation", 《SYNTHESIS》 * |
| MARTIN CONDA-SHERIDAN ET AL: "Potential Chemopreventive Agents Based on the Structure of the Lead Compound 2-Bromo-1-hydroxyphenazine, Isolated from Streptomyces Species, Strain CNS284", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 周湘云: "吩嗪硫酸甲酯合成法", 《宁夏医学院学报》 * |
| 杨荣华，张盼强: "利用RT培司生产废料合成吩嗪硫酸甲酯的研究", 《精细化工中间体》 * |
| 黄素萍: "二醋酸碘苯促进的水相反应及Cu（Ⅱ）/联咪唑催化的Sonogashira偶联反应研究", 《中国优秀硕士论文全文数据库 工程科技I辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974099A (en) * | 2015-07-23 | 2015-10-14 | 西安瑞联近代电子材料有限责任公司 | New synthesis method of phenazine |
| CN106699722A (en) * | 2016-12-26 | 2017-05-24 | 上海生农生化制品股份有限公司 | Synthetic method of 2,2-dichloro-1,3-benzodioxole-4-formaldehyde |
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Application publication date: 20121226 |