CN105669590A - Catalyst-free technique for synthesizing phenothiazine drug intermediate - Google Patents
Catalyst-free technique for synthesizing phenothiazine drug intermediate Download PDFInfo
- Publication number
- CN105669590A CN105669590A CN201610129578.6A CN201610129578A CN105669590A CN 105669590 A CN105669590 A CN 105669590A CN 201610129578 A CN201610129578 A CN 201610129578A CN 105669590 A CN105669590 A CN 105669590A
- Authority
- CN
- China
- Prior art keywords
- adjacent
- phenothiazines
- catalyst
- thiodiphenylamine
- phenothiazine
- 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.)
- Granted
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The invention provides a catalyst-free excellent-regioselectivity weak-alkali-prommoted technique for synthesizing a phenothiazine intermediate. The method comprises the following step: in an inert atmosphere, 2-acetaminophenyl S-thioacetate and o-dihalogenated aromatic hydrocarbons directly react in the presence of a weak alkali to obtain the phenothiazine drug intermediate. The technique is green and environment-friendly, has higher reaction yield of the intermediate for most phenothiazines, and has industrialized application prospects.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be exactly more particularly do not need catalyzer, under heating and weak base exist, S-thioacetic acid 2-kharophen phenyl ester and adjacent dihalo aromatic hydrocarbons are directly obtained by reacting phenothiazines pharmaceutical intermediate.
Background technology
Phenothiazines medicine, can be used as treatment mental disorder medicine, for schizophrenia or other psychotic disorders, common are: chlorpromazine, trilafon, Fluphenazine, thioridazine, prochlorperazine etc. Therefore, the synthesis developing phenothiazines pharmaceutical intermediate has actual value.
The method of synthesis phenothiazines intermediate is also fewer. The thiodiphenylamine of unsubstituted at high temperature can synthesize with sulfur cross-linking pentanoic under catalysis of iodine, but produces the hydrogen sulfide of a large amount of stench, severe toxicity. But what its derivative had can by synthesizing the derivative reaction of thiodiphenylamine, but synthetic route is often long. Phenothiazine derivative can also be realized by the sulfuration of diphenylamine derivatives, but general exist the positional isomers by product being difficult to the regioselective reaction of control and bringing, and had both affected product rate, and had also been difficult to separation. Phenothiazine compound can also carry out nucleophilic aromatic substitution by bromothiophenol and o-chloronitrobenzene, and the nitro that then reduces becomes amine, and then occurs the C-N coupling in molecule to obtain. Phenothiazine compound also has a kind of more common synthetic method, is namely reset by Smiles and synthesizes, has good regioselectivity, but synthetic route is very long.
Tornoe in 2008 and co-worker thereof report at Pd2(dba)3Under existing with the catalyzer of two (diphenylphosphine) ferrocene composition, adjacent bromo-iodobenzene compounds, fat or aromatic amine and 2-bromo thiophenol three kinds of components complete the reaction process of a C-S coupling and twice C-N coupling in a reactor, obtain phenothiazine compound (Angew.Chem.,Int.Ed.,2008, 47 (9), 1726-1728). The palladium reagent that the method for Tornoe uses and Phosphine ligands are all very expensive, production cost height.
Horse in 2010 greatly wait people report with the adjacent iodine arylamine of cheap CuI and proline(Pro) catalysis and adjacent bromine virtue thiophenol series connection C-S coupling and C-N linked reaction synthesis phenothiazine compound (Angew.Chem.Int.Ed.,2010, 49 (7), 1291-1294). The adjacent iodine arylamine of the raw material that horse method greatly uses and adjacent bromine virtue thiophenol may occur autoimmunity syndrome to generate by product under CuI catalysis; Reaction carries out in two steps, and the accumulative reaction times, speed of reaction was slow generally more than 100 hours.
Once celebrating pleasures in 2012 and co-worker thereof report the synthetic method of the phenothiazine compound of improvement, with the cross-coupling reaction synthesis phenothiazine compound of CuI catalysis near amino thiophenols and adjacent dihalo aromatic hydrocarbons, avoid autoimmunity syndrome (Chem.Commun., 2012 of raw material48, 5,367 5369).
Within 2015, Zhang reports adjacent FeSO4.7H2Cross-coupling reaction synthesis phenothiazine compound (J.Org.Chem.2015,80,6128 6132) of the kharophen thiophenol of O catalysis and adjacent dihalo aromatic hydrocarbons.
The people such as Tao in 2011 with without the ligand CuI bromo-N-of catalysis 2-(2-iodophenyl) aniline and thioacetamide carry out in a reactor continuous twice C-S coupling obtain thiodiphenylamine (Synlett,2011, (1), 134-138); But, its bromo-N-of raw material 2-(2-iodophenyl) aniline complex structure, need just can obtain through multistep synthesis.
This several synthetic method all needs transition-metal catalyst above. Deng and co-worker thereof report does not need transition-metal catalyst, from the method for cyclohexanone analog compound and near amino thiophenols synthesis phenothiazines intermediate, promote the addition in reaction process and dehydrogenation with additive potassiumiodide.
The present invention's report be do not need catalyzer, under weak base exists, S-thioacetic acid 2-kharophen phenyl ester and adjacent dihalo aromatic hydrocarbons are obtained by reacting phenothiazines pharmaceutical intermediate.
Summary of the invention
It is an object of the invention to provide the new synthetic method of a kind of phenothiazines pharmaceutical intermediate.
The present invention discloses does not need catalyzer, under weak base exists, S-thioacetic acid 2-kharophen phenyl ester and adjacent dihalo aromatic hydrocarbons are obtained by reacting phenothiazines pharmaceutical intermediate. The method is easy and simple to handle, and reaction conditions is gentle, and the time is shorter, and cheaper starting materials is easy to get, and product rate is general higher, is applicable to industrial production.
The experimental procedure of this synthetic method: in the reactor, adds a certain amount of inorganic weak bases, the adjacent kharophen phenyl ester of thioacetic acid-S-, adjacent dihalo aromatic hydrocarbons and solvent. Then, reactor inert gas replacement three times, is placed in reactor the oil bath stirring reaction certain time being preheating to certain temperature. Then, cancellation reaction after cool to room temperature, with organic solvent extraction, and then separation and purification obtains target product phenothiazine compound.
Embodiment
Set forth the present invention further below by embodiment, therefore do not limit the present invention among described scope of embodiments.
Embodiment 1
Get the rub oral examination tube of a drying, band magnetic agitation rod, add the N of 2mmol cesium carbonate, 0.5mmolS-thioacetic acid 2-kharophen phenyl ester, adjacent bromo-iodobenzene, 2mL, dinethylformamide, with the anti-mouth plug fastening sealing of rubber, Schlenk vacuum line vacuumizes with oil pump, is filled with argon replaces (repeating three times) again, then, test tube is put on magnetic stirring apparatus, the oil bath pan stirring reaction of preheating 150 DEG C 10 hours. After cool to room temperature, add 20mL shrend to go out reaction, extracting 3 secondary response mixtures with the mixed solvent 15mL of sherwood oil and the equal-volume ratio of ethyl acetate, organic phase is washed with 10mL again, organic phase anhydrous magnesium sulfate drying, filter, filtrate obtains crude product with Rotary Evaporators concentrating under reduced pressure, mixed solvent (from 10 to the 10 1) wash-out of crude product sherwood oil and ethyl acetate, the concentrated elutriant containing target compound, obtain the product thiodiphenylamine of purifying, product rate 81%. 10H-thiodiphenylamine, Mp:184-185 DEG C;1HNMR(300MHz,CD3Cl),δ(ppm):6.97-7.01(m,4H),6.80-6.85(m,2H),6.55(d,J=7.74Hz,2H),5.79(s,1H);13CNMR(75MHz,CD3COCD3),δ(ppm):143.3(2C),128.2(2C),127.1(2C),122.8(2C),118.3(2C),115.3(2C)。
Embodiment 2
Adopting similar synthetic method, adjacent two iodine benzene replace the adjacent bromo-iodobenzene in embodiment 1, obtain thiodiphenylamine product rate and are respectively 91%.
Embodiment 3
Adopting similar synthetic method, adjacent chloroiodobenzone replaces the adjacent bromo-iodobenzene in embodiment 1, obtains thiodiphenylamine product rate and is respectively 54%.
Embodiment 4
Adopting similar synthetic method, 4-nitro-1,2-dibromobenzene replaces the adjacent chloro-bromobenzene in embodiment 1, obtains 2-nitro thiodiphenylamine, product rate 63%.
Embodiment 5
Adopting similar synthetic method, 4-trifluoromethyl-2-iodine chlorobenzene replaces the adjacent bromo-iodobenzene in embodiment 1, obtains 3-trifluoromethyl thiodiphenylamine, product rate 65%. 3-(trifluoromethyl)-10H-thiodiphenylamine, Mp:215-216oC;1HNMR(300MHz,CD3COCD3),δ(ppm):8.12(s,1H),7.69-7.13(m,3H),6.94(d,J=5.20Hz,2H),6.83(t,J=7.40Hz,1H),6.71(d,J=7.98Hz,1H).
Embodiment 6
Adopting similar synthetic method, the bromo-4-of 2-fluoro-1-iodine benzene replaces the adjacent bromo-iodobenzene in embodiment 1, obtains 4-fluorine thiodiphenylamine, product rate 82%.
Embodiment 7
Adopting similar synthetic method, 3-bromo-4-iodo-benzoic acid methyl esters replaces the adjacent bromo-iodobenzene in embodiment 1, obtains thiodiphenylamine methyl-formiate, product rate 42%.
Embodiment 8
Adopting similar synthetic method, 2,3,3-Triiodobenzoic acid replaces the adjacent bromo-iodobenzene in embodiment 1, obtains 3-iodine thiodiphenylamine formic acid, product rate 73%. 3-iodine thiodiphenylamine formic acid,1HNMR(400MHz,DMSO-d6)δ8.96,7.17(d,J=8.0Hz,1H),7.09(m,2H),6.99(m,2H),6.86(dt,J=8.0Hz,2.0Hz,1H),6.72(dd,J=8.0Hz,2.0Hz,1H).
Embodiment 9
Adopting similar synthetic method, 1,2-bis-chloro-3-iodine benzene replaces the adjacent bromo-iodobenzene in embodiment 1, obtains 2-chloro phenothiazine, product rate 64%. 2-chloro-10H-thiodiphenylamine, Mp:197-198 DEG C;1HNMR(300MHz,CD3Cl), δ (ppm): 7.33-7.38 (m, 2H), 6.98-7.08 (m, 2H), 6.63-6.80 (m, 3H), 4.33 (s, 1H);13CNMR(75MHz,CD3COCD3),δ(ppm):144.6,144.2,133.3,128.5,128.1,127.2,123.4,122.4,117.9,117.3,115.6,114.9.
Embodiment 10
Adopting similar synthetic method, the bromo-5-of 1,3-bis-fluoro-2-iodine benzene replaces the adjacent bromo-iodobenzene in embodiment 1, obtains the bromo-4-fluorine thiodiphenylamine of 2-, product rate 65%.
Embodiment 11
Adopting similar synthetic method, the bromo-2-of 4-chloro-1-iodine benzene replaces the adjacent bromo-iodobenzene in embodiment 1, obtains 4-bromine thiodiphenylamine, product rate 70%.
Embodiment 12
Adopting similar synthetic method, the chloro-2-of 4-bromo-1-iodine benzene replaces the adjacent bromo-iodobenzene in embodiment 1, obtains 4-chloro phenothiazine, product rate 88%.
Embodiment 13
Adopting similar synthetic method, replace the solvent N in embodiment 1 with methyl-sulphoxide, dinethylformamide, obtains thiodiphenylamine, product rate 67%.
Embodiment 14
Adopt similar synthetic method, replace the weak base cesium carbonate in embodiment 1 with salt of wormwood, obtain thiodiphenylamine, product rate 72%.
Embodiment 15
Adopt similar synthetic method, replace the weak base cesium carbonate in embodiment 1 with anhydrous phosphoric acid potassium, obtain thiodiphenylamine, product rate 74%.
Claims (2)
1. the method for a catalyst-free synthesis phenothiazines pharmaceutical intermediate, it is characterised in that under an inert atmosphere, under weak base exists, S-thioacetic acid 2-kharophen phenyl ester and adjacent dihalo aromatic hydrocarbons coupling generation phenothiazines intermediate under heating.
2. the method for a kind of catalyst-free synthesis phenothiazines pharmaceutical intermediate according to claim 1, it is characterised in that said weak base is cesium carbonate, salt of wormwood, potassiumphosphate; Solvent is N, dinethylformamide, methyl-sulphoxide; S-thioacetic acid 2-kharophen phenyl ester: adjacent dihalo aromatic hydrocarbons: the mol ratio of alkali is 1:1.2:4; Reaction Heating temperature is 150 DEG C, and the reaction times is 10 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610129578.6A CN105669590B (en) | 2016-03-08 | 2016-03-08 | The technique of catalyst-free synthesis phenothiazines intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610129578.6A CN105669590B (en) | 2016-03-08 | 2016-03-08 | The technique of catalyst-free synthesis phenothiazines intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105669590A true CN105669590A (en) | 2016-06-15 |
| CN105669590B CN105669590B (en) | 2018-04-06 |
Family
ID=56307145
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610129578.6A Active CN105669590B (en) | 2016-03-08 | 2016-03-08 | The technique of catalyst-free synthesis phenothiazines intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105669590B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279063A (en) * | 2016-08-11 | 2017-01-04 | 于金龙 | A kind of synthetic method of medicine intermediate phenothiazine compound |
| CN113698362A (en) * | 2021-09-01 | 2021-11-26 | 南京杰运医药科技有限公司 | Preparation method of 2-cyanophenothiazine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532057A (en) * | 2011-11-17 | 2012-07-04 | 成都理工大学 | Copper catalytic synthesis phenothiazine compound |
| CN104529938A (en) * | 2014-12-26 | 2015-04-22 | 中山大学 | Novel method for synthesizing phenothiazine compounds |
-
2016
- 2016-03-08 CN CN201610129578.6A patent/CN105669590B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532057A (en) * | 2011-11-17 | 2012-07-04 | 成都理工大学 | Copper catalytic synthesis phenothiazine compound |
| CN104529938A (en) * | 2014-12-26 | 2015-04-22 | 中山大学 | Novel method for synthesizing phenothiazine compounds |
Non-Patent Citations (5)
| Title |
|---|
| CHRISTA S. BARKSCHAT，等: "Synthesis, Electronic Properties, and Self-Assembly on Au{111} of Thiolated Phenylethynyl Phenothiazines", 《CHEM.MATER.》 * |
| CHRISTOPH LAMBERT，等: "Heterogeneous Electron Transfer Processes in Self-Assembled Monolayers of Amine Terminated Conjugated Molecular Wires", 《LANGMUIR》 * |
| CHUAN DAI，等: "Synthesis of phenothiazines via ligand-free CuI-catalyzed cascade C–S and C–N coupling of aryl ortho-dihalides and ortho-aminobenzenethiols", 《CHEM. COMMUN.》 * |
| LABORATORIE DE CHIMID ORGANIQUE，等: "A Facile Synthesis of Cyanophenothiazines", 《J.HETEROCYCLIC CHEM.》 * |
| WEIYE HU，等: "Method for the Synthesis of Phenothiazines via a Domino Iron-Catalyzed C−S/C−N Cross-Coupling Reaction", 《J.ORG.CHEM.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279063A (en) * | 2016-08-11 | 2017-01-04 | 于金龙 | A kind of synthetic method of medicine intermediate phenothiazine compound |
| CN106279063B (en) * | 2016-08-11 | 2018-07-27 | 南京波普生物医药研发有限公司 | A kind of synthetic method of medicine intermediate phenothiazine compound |
| CN113698362A (en) * | 2021-09-01 | 2021-11-26 | 南京杰运医药科技有限公司 | Preparation method of 2-cyanophenothiazine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105669590B (en) | 2018-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103418438B (en) | A kind of azepine Cabbeen class palladium catalyst and its preparation method and application | |
| JP6910960B2 (en) | Chiral Spiro Ring Phosphine-Nitrogen-Sulfur Tridentate Ligand and Its Preparation Method and Application | |
| JP6878460B2 (en) | Its use in heterocyclic carboxylic acid amide ligands and copper-catalyzed coupling reactions of aryl halides | |
| CN105175327B (en) | A kind of synthetic method of quinoline | |
| CN102532057B (en) | Copper catalytic synthesis phenothiazine compound | |
| CN104803898A (en) | Aryl-alkyl and aryl-aryl thioether compound and synthesis method thereof | |
| CN107973778B (en) | A kind of ruthenium catalysis aromatic ketone replaces the methods and application of naphthalene derivatives with the more virtues of tolans cyclization preparation | |
| CN105175328B (en) | It is a kind of using aromatic amine, aromatic aldehyde, ketone synthesis of quinoline derivatives method | |
| CN110294704A (en) | A method of it prepares containing single fluoroalkyl vinyl hydrocarbon compound | |
| CN105669590A (en) | Catalyst-free technique for synthesizing phenothiazine drug intermediate | |
| CN109096162B (en) | Sc-catalyzed nucleophilic addition reaction method of mercaptan to o-methylenebenzoquinone | |
| CN104945294A (en) | Compound containing trifluoromethylthio group and preparation method thereof | |
| CN104557957B (en) | Synthetic method of spiro-oxoindole ethylene oxide derivative | |
| CN108395423A (en) | The synthetic method of 2- benzal tetrahydrothiophene derivatives | |
| CN104311508A (en) | Synthetic method of iron-catalyzed phenothiazine compound | |
| CN101633647A (en) | Method for synthesizing alpha-amino aryl alkyl ketone compound with high selectivity and high yield | |
| CN105622302A (en) | Synthesis method of substituted pyrogallols | |
| CN105949119B (en) | A method of polysubstituted 2 (the 1H)-quinolinones compound of synthesis | |
| CN105837528B (en) | A kind of preparation method of 2- (methyl sulphonyl) -10H- phenthazine | |
| Chen et al. | Nickel catalyzed decarboxylative alkylation of aryl triflates with anhydrides | |
| CN103183680A (en) | Method for preparing asenapine | |
| KR101540623B1 (en) | Novel preparation method of benzoxazole derivative | |
| CN105622544B (en) | A kind of synthetic method of N- sulfonyls -3,4- dihydro -2H-1,4- thiazines | |
| CN109456155A (en) | A method of tetralin ketone derivatives quickly being prepared based on substitution cyclobutanol oxidation open loop/cyclization | |
| CN108147996A (en) | A kind of synthetic method of aryl methylene double pyrazole ester monopotassium salt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200515 Address after: Room 1602, B1 Floor, Lijinxiu Jiangnan (West District), east of Gouyun Road, north of Yinhe No. 2 Road, Suzhou City, Anhui Province Patentee after: Suzhou Teng Teng Intellectual Property Advisory Co.,Ltd. Address before: 610041, 3, 1, 1480 north section of Tianfu Road, Chengdu high tech Zone, Sichuan Patentee before: SICHUAN MOKAI TECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221221 Address after: 100000 Room 401, Xinzhou Business Building, 58 Fucheng Road, Haidian District, Beijing Patentee after: Beijing Chengbaixin Biotechnology Co.,Ltd. Address before: Room 1602, B1 / F, Jinxiu Jiangnan (West District), east of Qingyun Road, north of Yinhe 2nd Road, Suzhou City, Anhui Province Patentee before: Suzhou Teng Teng Intellectual Property Advisory Co.,Ltd. |
|
| TR01 | Transfer of patent right |