CN114213359B - Method for synthesizing 1-hydroxy phenothiazine compounds - Google Patents
Method for synthesizing 1-hydroxy phenothiazine compounds Download PDFInfo
- Publication number
- CN114213359B CN114213359B CN202210032282.8A CN202210032282A CN114213359B CN 114213359 B CN114213359 B CN 114213359B CN 202210032282 A CN202210032282 A CN 202210032282A CN 114213359 B CN114213359 B CN 114213359B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- synthesizing
- compounds
- diphenyl sulfide
- 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
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
-
- 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 belongs to the technical field of organic synthesis, relates to a synthesis method of phenothiazine compounds, and in particular relates to a method for synthesizing 1-hydroxy phenothiazine compounds. O-mercaptoaniline compound and catechol compound are used as raw materials, the O-mercaptoaniline compound and the catechol compound are oxidized to be o-benzoquinone compound, S-substitution reaction is carried out on the o-benzoquinone compound and the o-mercaptoaniline compound to synthesize intermediate diphenyl sulfide compound, and the intermediate diphenyl sulfide compound is catalyzed to oxidize and dehydroxylate to form a ring to synthesize the 1-hydroxy phenothiazine compound. The invention has the advantages of simple synthetic route, easily obtained synthetic raw materials, mild reaction condition, high reaction efficiency, low price and high activity of the catalyst, simple post-treatment, less waste and stronger application prospect.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, relates to a synthesis method of phenothiazine compounds, and in particular relates to a method for synthesizing 1-hydroxy phenothiazine compounds.
Background
Phenothiazine compounds are a widely used class of tricyclic compounds containing nitrogen and sulfur. The number of clinically applied phenothiazines is not hundreds, and some phenothiazines show promising activities in the aspects of resisting cancer, resisting bacteria, treating Alzheimer disease and the like [ Krystian plus, et al European Journal of Medicinal Chemistry,2011,46,3179-3189]. In recent decades, phenothiazine compounds have great application prospects in the fields of organic dyes, chemiluminescent materials, chemical sensors and other materials. Because of their specific structure, the potential biological activity and photoelectric properties of the phenones, thiazines are of great interest. The synthesis of thiazines is very much described [ Ge rard Taurand et al, ullmann's Encyclopedia of Industrial Chemistry,2012, wiley-VCH Verlag GmbH & Co. KGaA, weinheim ], but the synthesis of 1-hydroxyphenothiazines is only recently reported, the only one being by the sulphur cyclization of 2-hydroxydiphenylamine (see formula one) [ a ] H.Ulrch, science of Synthesis,2004,17,117-221; b) Silberg et al Tetrahedron Letter,1974,43,3801-380; c) Schmitt, GB 839846 ].
This approach has several drawbacks, such as: high reaction temperature, low yield, complex separation and corrosive toxic gas H 2 S productionAnd the like, thereby limiting the use of these methods.
Disclosure of Invention
Aiming at the technical problems, the invention provides a method for synthesizing 1-hydroxy phenothiazine compounds, which takes o-mercaptoaniline compounds and catechol compounds as raw materials, the o-mercaptoaniline compounds are oxidized into o-benzoquinone compounds, the o-benzoquinone compounds and the o-mercaptoaniline compounds undergo S-substitution reaction to synthesize intermediate diphenyl sulfide compounds, and the intermediate diphenyl sulfide compounds undergo catalytic oxidation, dehydroxylation and cyclization three-step reaction to synthesize the 1-hydroxy phenothiazine compounds (shown as formula II).
In order to achieve the above purpose, the technical scheme of the invention is realized as follows:
a method for synthesizing 1-hydroxy phenothiazine compounds uses o-mercapto aniline compounds and catechol compounds as raw materials, the o-mercapto aniline compounds and catechol compounds are oxidized into o-benzoquinone compounds, the o-benzoquinone compounds and the o-mercapto aniline compounds are subjected to S-substitution reaction to synthesize intermediate diphenyl sulfide compounds and intermediate diphenyl sulfide compounds, and the intermediate diphenyl sulfide compounds are subjected to catalytic oxidation and dehydroxylation to form three-step reaction to synthesize the 1-hydroxy phenothiazine compounds.
Substituent R of o-mercaptoaniline compound, catechol compound and 1-hydroxy phenothiazine compound 1 、R 2 Is F, cl and OCH 3 、CH 3 、NO 2 Any one of tert-butyl.
The reaction of oxidizing catechol compound into o-benzoquinone compound refers to the oxidation of catechol compound into corresponding o-benzoquinone, and the oxidant is sodium periodate. Oxidizing catechol compounds into o-benzoquinone compounds by sodium periodate in a water phase under the ice water bath condition, and extracting by using dichloromethane to obtain a dichloromethane solution of the o-benzoquinone compounds; the solution is directly used for the next step of S-substitution reaction with o-mercaptoaniline without separation.
The S-substitution reaction of the o-benzoquinone compound and the o-mercaptoaniline compound refers to the reaction of the methylene dichloride solution of the o-benzoquinone compound obtained in the first step and the o-mercaptoaniline compound to generate the corresponding intermediate diphenyl sulfide compound. At room temperature, dropwise adding a dichloromethane solution of the o-benzoquinone compound into a dichloromethane solution of the o-mercaptoaniline compound, adding petroleum ether with equal volume, standing to separate out white solid, filtering, recrystallizing, and drying to obtain the intermediate diphenyl sulfide compound.
Wherein, the feeding mole ratio of the o-benzoquinone compound to the o-mercaptoaniline compound is 1:1.
The catalytic oxidation dehydroxylation cyclization reaction of the intermediate diphenyl sulfide compound refers to that the intermediate diphenyl sulfide compound obtained in the second step of reaction is subjected to intramolecular oxidation dehydroxylation cyclization reaction under the catalytic oxidation condition to generate the 1-hydroxy phenothiazine compound. Gallic acid and Mn (OAc) in a molar ratio of 1:1 2 Under the combined catalysis, the intermediate diphenyl sulfide compound reacts under the oxygen pressure of 0.3MPa to generate the 1-hydroxy phenothiazine compound.
Further, the solvent used in the catalytic oxidative dehydroxylation cyclization reaction is either ethanol or water or a water-alcohol mixed solvent, preferably a water-ethanol (v: v=1:1) mixed solvent. The increase of the solvent consumption can reduce the viscosity of the reaction liquid to improve the stirring effect and further improve the reaction effect, but the excessive solvent consumption can reduce the concentration of the catalytic system to reduce the reaction efficiency and increase the energy consumption. The dosage of the solvent is 10-30 times of the mass of the intermediate diphenyl sulfide compound.
Further, the dosage of the gallic acid catalyst is 0.1-5% of the dosage of the intermediate diphenyl sulfide compound substance, and the Mn (OAc) catalyst is used 2 The dosage of the catalyst is 0.1-5% of the dosage of the intermediate diphenyl sulfide compound substance.
Further, the intermediate diphenyl sulfide compound is subjected to catalytic oxidation and dehydroxylation cyclization reaction at the temperature of 20-60 ℃ for 1-10 hours.
After the three-step reaction is finished, the post-treatment process is not particularly limited, and the separation and purification of the product can be carried out by the following method: after the oxidation reaction is finished, the 1-hydroxy phenothiazine compound is obtained through the steps of evaporating an organic solvent, adding water for dilution, standing for precipitation of solid, suction filtration or centrifugal separation of solid, recrystallization, suction filtration, drying and the like.
The invention has the following beneficial effects:
1. the invention has simple synthetic route, can obtain the 1-hydroxy phenothiazine compound through three steps of reactions, and has easily obtained synthetic raw materials.
2. The reaction conditions of the invention are mild (the three reaction temperatures are respectively ice water bath, room temperature and 20-60 ℃); the post-treatment operation is simple, wherein the methylene dichloride solution of the o-benzoquinone compound in the step (1) can be directly used for the S-substitution reaction without separation; and (3) using a conventional post-treatment process to obtain intermediates and products.
3. The invention researches the influence of the solvent dosage in the step (3) on the catalytic oxidation dehydroxylation cyclization reaction, and discovers that: the increase of the solvent dosage can reduce the viscosity of the reaction liquid to improve the stirring effect and further improve the reaction effect, but the excessive dosage can reduce the concentration of the catalytic system to reduce the reaction efficiency and increase the energy consumption, so that the selection of the solvent with proper dosage plays an important role in improving the reaction effect.
4. The method has the advantages of high reaction efficiency (the highest yield of the 1-hydroxy phenothiazine compounds is 95%, the highest purity is 98%), low price of the catalyst, high activity, less waste, environmental friendliness and stronger application prospect.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is an intermediate 2-amino-2', 3 prepared in example 1 of the present invention' -dihydroxy-diphenyl sulfide 1 H NMR spectrum.
FIG. 2 is a schematic diagram of an intermediate 2-amino-2 ',3' -dihydroxy-diphenyl sulfide prepared in example 1 of the present invention 13 C NMR spectrum.
FIG. 3 is a schematic representation of 1-hydroxyphenothiazine prepared in example 1 of the present invention 1 H NMR spectrum.
FIG. 4 is a schematic illustration of 1-hydroxyphenothiazine prepared in example 1 of the present invention 13 C NMR spectrum.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without any inventive effort, are intended to be within the scope of the invention.
Example 1
Synthesis of o-benzoquinone:
1.1g catechol was dissolved in 20mL of methylene chloride to prepare a solution. In a 150mL three-necked flask, 2.2g of sodium periodate and 50mL of water are added, the solution is cooled and stirred in an ice water bath, catechol dichloromethane solution is rapidly added dropwise, stirring is continued for 10min, 3X 15mL of dichloromethane is used for extraction, and the two solutions are combined to obtain o-benzoquinone dichloromethane solution.
Synthesis of intermediate 2-amino-2 ',3' -dihydroxydiphenyl sulfide:
into a 250mL three-necked flask, 1.25g of o-mercaptoaniline and 50mL of methylene chloride were put, and the mixture was dissolved by stirring, followed by dropwise addition of the o-benzoquinone methylene chloride solution obtained in the above step. Half of the volume of dichloromethane was removed by rotary evaporation, the same volume of petroleum ether was added, the white solid was precipitated by standing, suction filtration and recrystallization of the solid, and after drying, 1.67g of white solid was obtained, the melting point was 117-118 ℃.
The product is determined to have a structure of an intermediate 2-amino-2 ',3' -dihydroxyl-diphenyl sulfide by NMR (see figures 1 and 2), HRMS and the like, the yield is 72%, and the purity of the product is 98% by analysis of a liquid chromatograph.
Synthesis of 1-hydroxy phenothiazine:
2.33g of intermediate 2-amino-2 ',3' -dihydroxyl-diphenyl sulfide, 24mg of gallic acid, 24mg of manganese acetate and 47mL of ethanol are put into a reaction kettle of 150mL, the mixture is heated to 60 ℃ under stirring, oxygen is introduced, the pressure in the reaction kettle is kept at 0.3MPa, the reaction is stopped after 1 hour, the reaction is stopped, the reaction kettle is cooled to room temperature, the ethanol is removed by rotary evaporation, the residual solid is recrystallized by isopropanol, the solution is filtered by suction, and dried, so that 2.04g of white solid with the melting point of 125-126 ℃ is obtained.
The product has a structure of 1-hydroxy phenothiazine determined by NMR (see figures 3 and 4), HRMS and the like, the yield is 95%, and the purity of the product analyzed by a liquid chromatograph is 98%.
Examples 2 to 11
Other intermediate diphenyl sulfide compound was synthesized in the same manner as in example 1, and other 1-hydroxyphenothiazine compound was synthesized in the same manner as in example 1, and various reaction conditions and reaction results are shown in Table 1.
TABLE 1 Synthesis of various 1-hydroxy phenothiazines under different conditions
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (7)
1. A method for synthesizing 1-hydroxy phenothiazine compounds is characterized by comprising the following steps:
(1) Oxidizing catechol compounds to generate o-benzoquinone compounds;
(2) S-substitution reaction is carried out on the o-benzoquinone compound obtained in the step (1) and the o-mercaptoaniline compound, and an intermediate diphenyl sulfide compound is synthesized;
(3) The intermediate diphenyl sulfide compound obtained in the step (2) is subjected to catalytic oxidation dehydroxylation cyclization reaction to synthesize a 1-hydroxy phenothiazine compound;
the catechol compound has a structural general formula shown in IO-mercaptoaniline compound has a structural general formula shown as II +.>The structural general formula of the 1-hydroxy phenothiazine compound is shown as III +.>The method comprises the steps of carrying out a first treatment on the surface of the Substituent R 1 、R 2 Is F, cl and OCH 3 、CH 3 、NO 2 Any one of tert-butyl;
the step (3) of catalyzing the oxidative dehydroxylation cyclization reaction to obtain gallic acid and Mn (OAc) 2 To a combined catalyst in which gallic acid and Mn (OAc) 2 The molar ratio of (2) is 1:1.
2. The method for synthesizing 1-hydroxyphenothiazine compounds according to claim 1, characterized in that: the oxidation reaction in the step (1) is carried out under the condition of ice water bath, and the catalyst adopted in the oxidation reaction is sodium periodate.
3. The method for synthesizing 1-hydroxyphenothiazine compounds according to claim 1, characterized in that: the S-substitution reaction in the step (2) is carried out in a dichloromethane solution, and the reaction temperature is room temperature.
4. The method for synthesizing 1-hydroxyphenothiazine compounds according to claim 1, characterized in that: in the step (2), the molar ratio of the o-benzoquinone compound to the o-mercaptoaniline compound is 1:1.
5. The method for synthesizing 1-hydroxyphenothiazine compounds according to claim 1, characterized in that: and (3) introducing oxygen into the reaction kettle in the step (3), wherein the condition of the catalytic oxidation dehydroxylation cyclization reaction is that the temperature is 20-60 ℃, the time is 1-10 hours, and the pressure is 0.3MPa.
6. The method for synthesizing 1-hydroxyphenothiazine compounds according to claim 5, characterized in that: the dosage of the catalyst gallic acid in the step (3) is 0.1-5 percent of the dosage of the intermediate diphenyl sulfide compound substance, and the catalyst Mn (OAc) 2 The dosage of the catalyst is 0.1-5% of the dosage of the intermediate diphenyl sulfide compound substance.
7. The method for synthesizing 1-hydroxyphenothiazine compounds according to claim 5, characterized in that: the solvent used in the catalytic oxidation dehydroxylation cyclization reaction in the step (3) is any one of ethanol and water or a water-alcohol mixed solvent, and the dosage of the solvent is 10-30 times of the mass of the intermediate diphenyl sulfide compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210032282.8A CN114213359B (en) | 2022-01-12 | 2022-01-12 | Method for synthesizing 1-hydroxy phenothiazine compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210032282.8A CN114213359B (en) | 2022-01-12 | 2022-01-12 | Method for synthesizing 1-hydroxy phenothiazine compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114213359A CN114213359A (en) | 2022-03-22 |
| CN114213359B true CN114213359B (en) | 2023-07-25 |
Family
ID=80708074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210032282.8A Active CN114213359B (en) | 2022-01-12 | 2022-01-12 | Method for synthesizing 1-hydroxy phenothiazine compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114213359B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3484745D1 (en) * | 1983-10-05 | 1991-08-01 | Merck Frosst Canada Inc | INHIBITORS FOR LEUKOTRIA BIOSYNTHESIS. |
| CN111205238B (en) * | 2020-03-13 | 2021-08-06 | 郑州大学 | Method for generating 2-aminophenol oxazine-3-ketone compound by catalyzing oxidation of molecular oxygen in aqueous phase |
-
2022
- 2022-01-12 CN CN202210032282.8A patent/CN114213359B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN114213359A (en) | 2022-03-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Guo et al. | One-pot three-component synthesis of functionalized spirooxindoles in gluconic acid aqueous solution | |
| Palermo et al. | Calix [n] arenes: active organocatalysts for the synthesis of densely functionalized piperidines by one-pot multicomponent procedure | |
| Maleki et al. | Room-temperature synthesis of 2-arylbenzothiazoles using sulfuric acid immobilized on silica as a reusable catalyst under heterogeneous conditions | |
| Vershinin et al. | Iron-catalyzed selective oxidative arylation of phenols and biphenols | |
| CN112574163A (en) | Method for synthesizing Brazilin natural product (+) -Brazilin | |
| CN112608296A (en) | Method for synthesizing brazilanin natural product Brazilane | |
| CN114380675A (en) | Method for synthesizing aryl phenol by reaction of halogenated aromatic hydrocarbon and phenol compound induced by visible light | |
| CA1077061A (en) | Process for the oxydation of .beta.-ethilenic ketones | |
| CN114349674B (en) | Thiourea compound and preparation method thereof | |
| CN113416150B (en) | Synthetic method of lobaplatin intermediate | |
| CN114213359B (en) | Method for synthesizing 1-hydroxy phenothiazine compounds | |
| CN102321063B (en) | Method for preparing unsymmetrical rhodamine | |
| CN112442008A (en) | Method for preparing 1, 4-dithiine and thiophene compounds by regulating elemental sulfur and active internal alkyne at temperature and conversion reaction of compound | |
| Kitani et al. | Synthesis and characterization of thiochromone S, S-dioxides as new photolabile protecting groups | |
| CN108276261B (en) | Method for preparing 2-bromofluorenone by catalyzing molecular oxygen oxidation in aqueous phase | |
| CN113999120B (en) | Preparation method of halogenated aniline compound | |
| CN112679521B (en) | Method for synthesizing mild azaspiro tricyclic framework molecule | |
| CN102127038B (en) | Method for synthetizing mono-thioether compound | |
| CN111454222B (en) | Synthesis method of 2,4- (1H, 3H) -quinazolinedione and derivatives thereof | |
| CN111229312B (en) | Solvent-free catalyst and preparation method and application thereof | |
| CN110724080B (en) | Synthetic method of aryl selenium cyanogen compound | |
| CN109180607B (en) | Method for synthesizing thiazine diketone heterocyclic compound by catalyzing carbonyl sulfide conversion with organic catalyst | |
| Ito et al. | 4-diazomethyl-7-methoxycoumarin as a new type of stable aryldiazomethane reagent | |
| CN115340469B (en) | Preparation method of diphenyl diazene or derivative thereof | |
| CN113861202B (en) | Large-scale preparation process of pterosin |
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 |