CN113816912B - Preparation method of phenazine - Google Patents
Preparation method of phenazine Download PDFInfo
- Publication number
- CN113816912B CN113816912B CN202111004807.9A CN202111004807A CN113816912B CN 113816912 B CN113816912 B CN 113816912B CN 202111004807 A CN202111004807 A CN 202111004807A CN 113816912 B CN113816912 B CN 113816912B
- Authority
- CN
- China
- Prior art keywords
- phenazine
- phenylenediamine
- organic solvent
- producing
- mixing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/46—Phenazines
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a preparation method of phenazine, and belongs to the technical field of organic synthesis. O-phenylenediamine is taken as a raw material and reacts with thionyl chloride in the presence of triethylamine to obtain 2,1,3-benzothiadiazole; then reacting with a brominating reagent to obtain 4,7-dibromobenzothiadiazole; then mixing with an organic solvent, adding magnesium metal to generate a Grignard reagent, quenching with acid water, and reducing with tin dichloride to obtain 3-bromo-o-phenylenediamine; then mixing with organic solvent, and reacting with air or oxygen under alkaline condition to obtain the phenol oxazine. The method is simple and convenient to operate, safe and stable, the intermediate in each step has economic benefits, the purity of the obtained product is high, expensive reagents or catalysts are avoided, and the method has potential industrial amplification prospects.
Description
Technical Field
The invention relates to a preparation method of phenazine, belonging to the technical field of medical intermediates.
Background
Phenazine CAS:92-82-0, english name: phenazine, also known as benzodiazepine (hetero) anthracene, dibenzopyrazine, is a dibenzocyclic pyrazine and also a starting material for many dyes, such as diaminoazine, neutral red, paraazaanthracene blue, and safranin. The method is mainly used for dye, medicine, organic synthesis intermediates and biochemical research.
Phenazines are a class of natural and synthetic nitrogen-containing heterocyclic compounds. Phenazine natural products are secondary metabolites of pseudomonas, streptomyces, and some other species of soil and marine organisms. Studies have shown that organisms that produce phenazines have a longer life span than organisms that do not produce phenazines, probably because the antibiotic activity of phenazines kills other microorganisms and improves survival conditions to protect the organism. The biological activities of the phenazines, such as antibiosis, anticancer, antimalarial and antiparasitic, are mainly that the phenazines have physiological functions of inhibiting and controlling the synthesis of DNA, RNA and protein and interrupting metabolic processes.
At present, the preparation method of the phenazine is many, and the phenazine is prepared by adopting 2-iodoaniline or 2-bromoaniline and copper sulfonate complex to react for 30 hours at the high temperature of potassium carbonate, TBAB and water [ Journal of Organometallic Chemistry,2012, vol.705, p.75-78 ]. The yield thereof was found to be 79%. In the method, the raw material 2-iodoaniline or 2-bromoaniline is easy to obtain, but the copper sulfonate complex is difficult to synthesize and is not easy to buy. The reaction equation is as follows:
the compound is synthesized by reacting ligand with palladium acetate and alkaline cesium carbonate at 110 ℃ for 15 hours, and the yield is 89% [ European Journal of Organic Chemistry,2013, #36, p.8330-8335]. The method uses expensive ligand and palladium acetate, and the obtained phenazine needs to remove palladium, which is not beneficial to large-scale production. The reaction equation is as follows:
therefore, it is necessary to deeply research the synthesis process of phenazine and provide a better, easily available, safe, stable and economical reaction route to meet the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention takes o-phenylenediamine as a raw material, and the o-phenylenediamine is reacted with thionyl chloride in the presence of triethylamine to obtain 2,1,3-benzothiadiazole; then reacting with a brominating reagent to obtain 4,7-dibromobenzothiadiazole; then mixing with organic solvent, adding magnesium metal to generate Grignard reagent, and quenching with acid water to eliminate one molecule of bromine. Reducing the reaction product with tin dichloride to obtain 3-bromo-o-phenylenediamine; then mixing with organic solvent, and reacting with air or oxygen under alkaline condition to obtain the phenol oxazine. The method is simple and convenient to operate, safe and stable, the intermediate in each step has economic benefits, the purity of the obtained product is high, expensive reagents or catalysts are avoided, and the method has potential industrial amplification prospects.
The preparation method of the phenazine comprises the following steps:
the first step is as follows: mixing o-phenylenediamine, triethylamine and dichloromethane, slowly dropwise adding thionyl chloride, and performing aftertreatment to obtain 2,1,3-benzothiadiazole;
the second step is that: mixing 2,1,3-benzothiadiazole with an organic solvent, adding or dropping a brominating agent in batches, quenching sodium bisulfite to obtain a crude product, and purifying to obtain 4,7-dibromobenzothiadiazole;
the third step: mixing metal magnesium with an organic solvent, slowly dropwise adding a solution containing 4,7-dibromobenzothiadiazole, quenching with hydrochloric acid, and adding tin dichloride for reduction to obtain 3-bromo-o-phenylenediamine;
the fourth step: mixing 3-bromine-o-phenylenediamine, inorganic base and organic solvent, heating to 100-120 ℃, introducing air or oxygen for reaction, and purifying to obtain the phenazine.
The fourth reaction step is to eliminate 3-bromo-o-phenylenediamine in inorganic alkali and oxygen condition to produce transition state phenylalkyne precursor, and to react to obtain phenazine.
Further, in the above technical scheme, in the first step, the molar ratio of o-phenylenediamine, triethylamine and thionyl chloride is 1:4.0-4.1:2.1-2.2.
Further, in the above technical solution, in the second step, the organic solvent is selected from dichloromethane or methanol, and the brominating agent is selected from NBS or bromine.
Further, in the technical scheme, the molar ratio of 2,1,3-benzothiadiazole to brominating reagent is 1.
Further, in the above technical solution, in the third step, the 4,7-dibromobenzothiadiazole, magnesium metal and tin dichloride molar ratio is 1:1.0-1.05:4.2-4.5.
Further, in the above technical solution, in the fourth step, the organic solvent is selected from dimethyl sulfoxide or sulfolane, and the inorganic base is selected from potassium carbonate.
Further, in the above technical scheme, the molar ratio of 3-bromo-o-phenylenediamine to potassium carbonate is 1:4.5-5.0.
Further, in the above technical scheme, in the fourth step of post-treatment, quenching with hydrochloric acid and adjusting pH =8-9, adding ethyl acetate for extraction, washing with water to obtain a crude product, and performing flash column chromatography (dichloromethane elution) on the crude product to obtain dichloromethane: n-heptane =1:4 beating to obtain light yellow crystal.
Advantageous effects of the invention
Compared with the prior synthesis method, the invention has the following beneficial effects:
1) The invention has simple requirement on equipment, avoids using complex or expensive noble metal reagent which is not easy to purchase, and reduces the cost.
2) The obtained phenazine is easy to purify, and each intermediate can be sold, thereby being in line with the production benefits of enterprises.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example 1
To a 500mL round bottom flask was added a solution of 32.4g (0.3 mol) of o-phenylenediamine and 121.4g (1.2 mol) of triethylamine in 200mL of dichloromethane. The temperature was reduced to 10 ℃ and a solution of thionyl chloride 78.5g (0.66 mol) in 100mL of dichloromethane was slowly added dropwise. After the dropwise addition, the temperature is naturally raised to the room temperature, the reaction is carried out for 2 hours, the HPLC detection raw material is less than 2%, the solvent is removed by distillation under reduced pressure, toluene is added for replacing 3 times, 100mL of ethanol is added, 300g of water is added, the temperature is reduced to the room temperature, the filtration is carried out, the filter cake is dried to obtain 37.9g of 2,1,3-benzothiadiazole, 98.6% of HPLC, and the yield is 92.7%. 1 H NMR(CDCl3,400MHz):8.04-8.00(m,2H),7.62-7.57(m,2H).
Example 2
To a 500mL round bottom flask, 27.2g (0.2 mol) of benzothiadiazole and 200mL of dichloromethane were added. Controlling the temperature at 15-20 ℃, adding 78.3g (0.44 mol) of N-bromosuccinimide into 20 parts of the mixture, reacting for 3 hours, detecting the raw material by HPLC (high performance liquid chromatography) to be less than 1%, adding saturated sodium bisulfite for quenching, layering, decompressing and concentrating to remove dichloromethane, adding 70mL of ethanol, adding 210g of water, cooling to room temperature, filtering, leaching a filter cake by water, drying to obtain 4,7-dibromobenzothiadiazole 53.1g, and obtaining HPLC 98.2% with the yield of 90.3%. 1 H NMR(400MHz,CDCl3):7.74-7.72(m,2H).
Example 3
To a 500mL round bottom flask, 27.2g (0.2 mol) of benzothiadiazole, 0.5g of chloroacetyl chloride, and 200mL of methanol were added. Controlling the temperature at 0-5 ℃, dropwise adding 72g (0.45 mol) of bromine/50 mL of methanol solution, reacting for 6 hours, detecting that the raw material is less than 4% by HPLC, adding saturated sodium bisulfite for quenching, concentrating under reduced pressure, adding 180g of water, cooling to room temperature, filtering, leaching a filter cake by using cold 10% methanol water solution, and drying to obtain 4,7-dibromobenzothiadiazole 55.3g, HPLC 95.1%, and the yield is 94.1%.
Example 4
To a 1000mL round bottom flask, under nitrogen, was added metallic magnesium (0.205 mol), iodine 0.1g, 4,7-dibromobenzothiadiazole 5.9g (0.02 mol), and 100mL tetrahydrofuran. Raising the temperature to be 25-35 ℃ for initiation, dropwise adding the remaining 4,7-dibromobenzothiadiazole 52.9g (0.18 mol)/250 mL tetrahydrofuran solution, raising the temperature to 55 ℃ for reaction for 6 hours, reducing the temperature to 0 ℃ after quenching, adding 10% hydrochloric acid for quenching, adjusting the pH to be 1.0-1.5, and adding163.1g of tin dichloride powder was charged, reacted for 2 hours, followed by TLC to detect no intermediate, 30% aqueous sodium hydroxide solution was added to adjust pH =12-13, MTBE was extracted, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and n-heptane was added to obtain 31g of 3-bromo-o-phenylenediamine, HPLC97.7%, yield 83%. 1 HNMR(400MHz,DMSO-d6):7.44-7.42(m,1H),6.78-6.76(m,1H),6.62-6.60(m,1H),4.94(s,2H).4.84(s,2H).
Example 5
Adding 18.7g (0.1 mol) of 3-bromo-o-phenylenediamine, 69.1g (0.5 mol) of ground potassium carbonate and 150mL of dimethyl sulfoxide into a 500mL reaction bottle, stirring and heating to 75-80 ℃, introducing oxygen into a bottom inserting tube, heating to 110 ℃, reacting for 14 hours, reducing the temperature to 20 ℃ when no raw material is left by HPLC (high performance liquid chromatography), adding concentrated hydrochloric acid to regulate the pH to be 7.0-7.5, layering, adding ethyl acetate into an aqueous phase to extract once, combining organic phases, washing with an aqueous solution of sodium bicarbonate for 2 times, concentrating the organic phase to a non-flowing solution, adding 200mL dichloromethane to dissolve, quickly passing through silica gel, leaching with dichloromethane for multiple times, concentrating an eluent, adding n-heptane, cooling and stirring, filtering to obtain 7.1g of faint yellow crystal phenazine, wherein the yield is 77.4%, and HPLC:99.2 percent. 1 HNMR(400MHz,DMSO-d6):8.27-8.25(m,4H),7.86-7.84(m,4H).
Example 6
Adding 18.7g (0.1 mol) of 3-bromo-o-phenylenediamine, 62.2g (0.45 mol) of ground potassium carbonate and 150mL of sulfolane into a 500mL reaction bottle, stirring and heating to 75-80 ℃, introducing air into a bottom inserting tube, heating to 120 ℃, reacting for 18 hours, reducing the temperature to 20 ℃ when no raw material is left by HPLC (high performance liquid chromatography), adding concentrated hydrochloric acid to regulate the pH to be 7.0-7.5, layering, adding ethyl acetate into an aqueous phase to extract once, combining organic phases, washing for 2 times by using 8% sodium bicarbonate aqueous solution, concentrating the organic phase to a non-flowing liquid, adding 200mL dichloromethane to dissolve, quickly passing through silica gel, leaching for multiple times by using dichloromethane, concentrating an eluent, adding n-heptane, cooling and stirring, filtering to obtain 7.2g of faint yellow crystal phenazine, wherein the yield is 79.4%, and HPLC:99.3 percent.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (8)
1. The preparation method of the phenazine is characterized by comprising the following steps:
the first step is as follows: mixing o-phenylenediamine, triethylamine and dichloromethane, slowly dropwise adding thionyl chloride, and performing aftertreatment to obtain 2,1,3-benzothiadiazole;
the second step is that: mixing 2,1,3-benzothiadiazole with an organic solvent, adding or dropping a brominating agent in batches, quenching sodium bisulfite to obtain a crude product, and purifying to obtain 4,7-dibromobenzothiadiazole;
the third step: mixing metal magnesium with an organic solvent, slowly dropwise adding a solution containing 4,7-dibromobenzothiadiazole, quenching with hydrochloric acid, and adding tin dichloride for reduction to obtain 3-bromo-o-phenylenediamine;
the fourth step: mixing 3-bromine-o-phenylenediamine, inorganic base and organic solvent, heating to 100-120 ℃, introducing air or oxygen for reaction, and purifying to obtain the phenazine.
2. The process for producing a phenazine according to claim 1, wherein: in the first step, the molar ratio of o-phenylenediamine, triethylamine and thionyl chloride is 1:4.0-4.1:2.1-2.2.
3. The process for producing a phenazine according to claim 1, wherein: in the second step, the organic solvent is selected from dichloromethane or methanol, and the brominating agent is selected from NBS or bromine.
4. A process for the preparation of a phenazine in accordance with claim 1, characterized in that: in the second step, the molar ratio of 2,1,3-benzothiadiazole to brominating reagent is 1.
5. The process for producing a phenazine according to claim 1, wherein: in the third step, the organic solvent is selected from 4,7-dibromobenzothiadiazole, magnesium metal and tin dichloride with the molar ratio of 1:1.0-1.05:4.2-4.5.
6. The process for producing a phenazine according to claim 1, wherein: in the fourth step, the organic solvent is selected from dimethyl sulfoxide or sulfolane, and the inorganic base is selected from potassium carbonate.
7. The process for producing a phenazine according to claim 6, wherein: in the fourth step, the molar ratio of the 3-bromine-o-phenylenediamine to the potassium carbonate is 1:4.5-5.0.
8. The process for producing a phenazine according to claim 1, wherein: and step four, carrying out post-treatment, quenching by adopting hydrochloric acid, adjusting the pH to be =8-9, adding ethyl acetate for extraction, washing by water, and carrying out flash column chromatography on a crude product, wherein dichloromethane: n-heptane =1:4 beating to obtain light yellow crystals.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111004807.9A CN113816912B (en) | 2021-08-30 | 2021-08-30 | Preparation method of phenazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111004807.9A CN113816912B (en) | 2021-08-30 | 2021-08-30 | Preparation method of phenazine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113816912A CN113816912A (en) | 2021-12-21 |
| CN113816912B true CN113816912B (en) | 2023-02-28 |
Family
ID=78913805
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111004807.9A Active CN113816912B (en) | 2021-08-30 | 2021-08-30 | Preparation method of phenazine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113816912B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130005933A1 (en) * | 2010-04-23 | 2013-01-03 | Ocean' S King Lighting Science & Technology Co., Ltd. | Copolymer comprising anthracene and benzoselenadiazole, preparing method and uses thereof |
| 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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0674255B2 (en) * | 1986-06-13 | 1994-09-21 | 広栄化学工業株式会社 | Process for producing compound containing pyrazine nucleus |
| KR101612903B1 (en) * | 2013-04-09 | 2016-04-19 | 희성소재 (주) | Phenazine-based compound and organic light emitting device comprising the same |
| CN111689866A (en) * | 2019-03-15 | 2020-09-22 | 中石化南京化工研究院有限公司 | Preparation method of tower reaction RT base |
-
2021
- 2021-08-30 CN CN202111004807.9A patent/CN113816912B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130005933A1 (en) * | 2010-04-23 | 2013-01-03 | Ocean' S King Lighting Science & Technology Co., Ltd. | Copolymer comprising anthracene and benzoselenadiazole, preparing method and uses thereof |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| A New Route to N-Substituted o-Phenylenediamines;E. S. LANE等;《Journal of the Chemical Society》;19551231;第1468-1470页 * |
| Synthesis and Physico-Chemical Properties in Aqueous Medium of All Possible Isomeric Bromo Analogues of Benzo-1H-Triazole,Potential Inhibitors of Protein Kinases;Romualda Wąsik等;《Journal of Physical Chemistry B》;20120525;第116卷(第24期);第7259-7268页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113816912A (en) | 2021-12-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112574163B (en) | Method for synthesizing Brazilin natural product (+) -Brazilin | |
| CN112778147B (en) | Preparation method of 2-amino-3-methyl-5-chlorobenzoic acid | |
| CN104250232A (en) | Preparation method of parecoxib sodium | |
| CN111704573B (en) | Preparation method of rabeprazole chloride and intermediate thereof | |
| CN106699570A (en) | Synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone | |
| CN112608296A (en) | Method for synthesizing brazilanin natural product Brazilane | |
| CN113816912B (en) | Preparation method of phenazine | |
| CN111574444A (en) | Preparation method of bedaquiline | |
| CN107011354B (en) | Preparation method of 5-isosorbide mononitrate | |
| CN112939891B (en) | Method for preparing biphenyl benzothiazole compound | |
| CN101696185B (en) | Synthesizing method of 6-nitro-S-(-)-indoline-2-carboxylic acid | |
| CN114989061A (en) | Preparation method of brivaracetam | |
| CN104974173B (en) | A kind of gulf embedding pentatomic sulphur heterocycle in position and hexa-atomic oxa- ring 3,4:The preparation method of 9,10 perylene tetracarboxylic acid N-butyls | |
| CN109942456B (en) | Method for synthesizing p-benzoquinone monoimine from p-aminophenol | |
| CN113234080A (en) | Sitagliptin phosphate intermediate impurity and preparation method thereof | |
| CN108299466B (en) | Improved dolutegravir synthesis method | |
| CN116589475B (en) | Preparation method of 2',4',5',7' -tetrachloro-5 (6) -carboxyl-4, 7-dichloro fluorescein | |
| CN113956268B (en) | 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method | |
| CN101805265A (en) | Synthesis method of 2-nitro-4-substituted phenylacetic acid | |
| CN112679361B (en) | Synthetic method of 3-fluoro-5-nitropyridine-2-formaldehyde | |
| CN104876917B (en) | The synthetic method of triazolone as fatty acid sythetase inhibitor | |
| CN111233616A (en) | Pyrenyl [4] helicene and synthesis method and application thereof | |
| WO2023216317A1 (en) | Method for synthesizing nirmatrelvir intermediate | |
| CN116621804B (en) | Chemical kinetics resolution method of 5-and 6-carboxyfluorescein compound isomer | |
| CN115974879B (en) | Preparation method of polysubstituted imidazo heterocyclic compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |