CN104829553A - New method of synthesizing 2,4-di-substituted benzothiazole - Google Patents
New method of synthesizing 2,4-di-substituted benzothiazole Download PDFInfo
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- CN104829553A CN104829553A CN201510113365.XA CN201510113365A CN104829553A CN 104829553 A CN104829553 A CN 104829553A CN 201510113365 A CN201510113365 A CN 201510113365A CN 104829553 A CN104829553 A CN 104829553A
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- CN
- China
- Prior art keywords
- new method
- benzothiazole
- synthesizing
- thiazole
- pivaloyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
A new method of synthesizing 2,4-di-substituted benzothiazole is disclosed, wherein R and R' both can be aryl groups, alkyl groups and heterocyclic ring groups. The method includes the steps of mixing a substituted thioamide substrate and a fluorine-containing alkali with a reaction solvent 1,4-dioxane, adding a known benzyne precursor slowly into the reaction solution to prepare 2,4-di-substituted benzothiazole, and performing column chromatographic purification to obtain a finish product of which the yield is 75%. The new method is low in raw material cost and the raw material is easy to obtain. The new method is simple in operation, is less in synthetic steps, is high in yield and has important application value in the fields of pharmaceutical chemistry and organic synthesis.
Description
Technical field
The present invention proposes a kind of synthesis 2,4-disubstituted benzenes and the novel method of thiazole.
Background technology
Benzothiazole, at organic synthesis, functional materials, spices, particularly has a wide range of applications in organic synthesis and pharmaceutical chemistry.Benzothiazole itself has very strong biological activity, is the important intermediate of synthesizing antitumor, antiepileptic drug and anti-inflammation drugs traditionally, has also been applied to antimicrobial drug, antiphlogistic drug, in diabetes medicament.The research in this year finds, 2,4-disubstituted benzenes thiazole, especially have the structure of a hydroxy-acid group or amide group can have certain restraining effect to poly (ADP-ribose) polymerase (PARP) target spot in No. 4 positions of benzothiazole, and PARP is the popular target spot of Recent study antitumor drug.
2,4-disubstituted benzenes the traditional preparation methods of thiazole, process is loaded down with trivial details, and productive rate is low.Wherein method is obtained by reacting a benzamide by 2-bromaniline and Benzoyl chloride, then benzamide is changed into thiobenzamide, then passes through K
3fe (CN)
6effect thiobenzamide is closed ring and prepares 4-bromo benzothiazole, by the cyanalation reaction of copper catalysis, bromine is changed into cyano group, then hydrolysis preparation 4-amide group benzothiazole.Another kind method reacts obtained benzamide from 2-Methyl anthranilate and Benzoyl chloride, closes ring and prepare 4-ester group benzothiazole after changing into thiobenzamide, but pass ring step productive rate is very low.
This patent proposes a kind of synthesis 2,4-disubstituted benzenes and the novel method of thiazole, compares traditional synthetic method, shortens synthesis step greatly, improve synthetic yield.More adapt to modern chemistry, the requirement of economical and efficient in pharmaceutical synthesis.
Summary of the invention
1, main purpose of the present invention: in view of 2,4-disubstituted benzenes and thiazole has important purposes, but existing synthetic method is complicated and productive rate is very low.The present invention utilizes novel benzyne reagent and thioamides substrate reactions, and a step obtains 2,4-disubstituted benzenes and thiazole, and productive rate is higher.Obtaining 2,4-different disubstituted benzenes and thiazole by changing substituted radical, will important using value be had in drug molecule synthesis and natural product synthesis field.
2, principle of the present invention: with the thioamides containing substituted radical for substrate, sulfo-substrate and a kind of aryne precursor carbonyl in two step nucleophilic substitution reactions and a step molecule occur and move, and obtain 2,4-disubstituted benzenes and thiazole.
Embodiment:
Below in conjunction with concrete reaction, further illustrate the present invention.With R ' for pivaloyl, R is phenyl is example.
By the thioamides substrate (88.6mg that pivaloyl is protected; 0.4mmol; 1.0equiv.), CsF (304mg, 2mmol, 5.0equiv.) is dissolved in 1; in 4-dioxane (30mL) reaction solvent; again by 1 of TPBT (268.0mg, 0.6mmol, 1.5equiv.); 4-dioxane (10mL) solution slowly joined in reaction solution through 8 hours at 80 DEG C, mixed and reacted.
Aftertreatment: after reaction terminates, remove solvent with Rotary Evaporators, obtain product 2-phenyl-4-pivaloyl benzothiazole through silica gel chromatography column separating purification, productive rate is 75%.
Accompanying drawing explanation
Fig. 1 is the synthesis of 2-phenyl-4-pivaloyl benzothiazole
Compound property
2-phenyl-4-pivaloyl benzothiazole
Mp:99-102℃；
1H NMR(500MHz,CDCl
3)δ8.07(m,2H),7.91(d,J＝8.0Hz,1H),7.49-7.47(m,3H),7.37(t,J＝7.5Hz,1H),7.28(d,J＝6.5Hz,1H),1.38(s,9H)ppm；
13C NMR(125MHz,CDCl
3)δ213.3,168.3,150.1,136.6,135.7,133.6,131.3,129.2,127.8,124.8,123.4,122.4,45.2,27.4ppm；IR(thin film)2966,2930,2866,1683,1570,1477,1445,1398,1364,1315,1279,1230,1173,1077,1037,998,964,768,755,736,705(cm
-1)；HRMS-MALDI(m/z)calcd for[C
18H
18NOS]
+,296.1109；found,296.1107.
The medicine used
Claims (1)
1. one kind is synthesized 2,4-disubstituted benzenes and the novel method of thiazole
2.2,4-disubstituted benzenes the synthesis of thiazole (with 2-phenyl-4-pivaloyl benzothiazole synthesize example), feature is, concrete steps are as follows:
The thiobenzamide of pivaloyl protection and cesium fluoride (CsF) are 1; 4-dioxane (1; 4-dioxane); at 80 DEG C; add a kind of benzyne reagent (TPBT) and react; obtaining 2-phenyl-4-pivaloyl benzothiazole, is 75% through column chromatography purification productive rate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510113365.XA CN104829553A (en) | 2015-03-16 | 2015-03-16 | New method of synthesizing 2,4-di-substituted benzothiazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510113365.XA CN104829553A (en) | 2015-03-16 | 2015-03-16 | New method of synthesizing 2,4-di-substituted benzothiazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104829553A true CN104829553A (en) | 2015-08-12 |
Family
ID=53807796
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510113365.XA Pending CN104829553A (en) | 2015-03-16 | 2015-03-16 | New method of synthesizing 2,4-di-substituted benzothiazole |
Country Status (1)
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| CN (1) | CN104829553A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105820137A (en) * | 2016-03-25 | 2016-08-03 | 重庆大学 | Novel method for synthesizing ortho diamido aromatic hydrocarbon through domino aryne precursor |
| CN107935927A (en) * | 2017-12-01 | 2018-04-20 | 重庆大学 | A kind of synthesis of the more yuan of rings of benzo-aza |
| CN109293599A (en) * | 2018-11-29 | 2019-02-01 | 福建医科大学 | A kind of method of microwave radiation benzo thioamide analog compound synthesis benzothiazole in water phase |
Citations (5)
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| US3787496A (en) * | 1971-04-29 | 1974-01-22 | Exxon Research Engineering Co | Preparation of aromatic compounds via benzyne intermediates |
| JP2002220396A (en) * | 2001-01-29 | 2002-08-09 | Japan Science & Technology Corp | Benzoic acid ester derivative and method for manufacturing it |
| US20090087721A1 (en) * | 2007-09-28 | 2009-04-02 | Yoshida Kenta | Surface-modified carbon material and method for producing the same |
| CN104177395A (en) * | 2014-07-31 | 2014-12-03 | 重庆大学 | Benzyne precursor and synthesis method thereof |
| CN104327001A (en) * | 2014-09-23 | 2015-02-04 | 兰州大学 | Aryne synthetic method |
-
2015
- 2015-03-16 CN CN201510113365.XA patent/CN104829553A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3787496A (en) * | 1971-04-29 | 1974-01-22 | Exxon Research Engineering Co | Preparation of aromatic compounds via benzyne intermediates |
| JP2002220396A (en) * | 2001-01-29 | 2002-08-09 | Japan Science & Technology Corp | Benzoic acid ester derivative and method for manufacturing it |
| US20090087721A1 (en) * | 2007-09-28 | 2009-04-02 | Yoshida Kenta | Surface-modified carbon material and method for producing the same |
| CN104177395A (en) * | 2014-07-31 | 2014-12-03 | 重庆大学 | Benzyne precursor and synthesis method thereof |
| CN104327001A (en) * | 2014-09-23 | 2015-02-04 | 兰州大学 | Aryne synthetic method |
Non-Patent Citations (7)
| Title |
|---|
| DACHUAN QIU ET AL: "Domino Aryne Precursor: A Step beyond the Boundary of Traditional Aryne Chemistry", 《SYNLETT》 * |
| JIARONG SHI ET AL: "Domino Aryne Precursor: Efficient Construction of 2,4-Disubstituted Benzothiazoles", 《J.AM.CHEM.SOC.》 * |
| NADALE K.DOWNER-RILEY ET AL: "Conversion of thiobenzamides to benzothiazoles via intramolecular cyclization of the aryl radical cation", 《TETRAHEDRON》 * |
| YUESI FANG ET AL: "Formation of Acridones by Ethylene Extrusion in the Reaction of Arynes with β-Lactams and Dihydroquinolinones", 《J ORG CHEM》 * |
| ZHIJIAN LIU ET AL: "Intermolecular C-N Addition of Amides and S-N Addition of Sulfinamides to Arynes", 《J.AM.CHEM.SOC.》 * |
| 李鹏宇 等: "苯并噻唑类杂环合成最新进展", 《精细化工中间体》 * |
| 竺宁 等: "2-取代苯并噻唑类衍生物合成方法研究的新进展", 《有机化学》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105820137A (en) * | 2016-03-25 | 2016-08-03 | 重庆大学 | Novel method for synthesizing ortho diamido aromatic hydrocarbon through domino aryne precursor |
| CN105820137B (en) * | 2016-03-25 | 2018-10-30 | 重庆大学 | A method of synthesizing two aminated aromatic hydrocarbons of ortho position using domino aryne precursor |
| CN107935927A (en) * | 2017-12-01 | 2018-04-20 | 重庆大学 | A kind of synthesis of the more yuan of rings of benzo-aza |
| CN109293599A (en) * | 2018-11-29 | 2019-02-01 | 福建医科大学 | A kind of method of microwave radiation benzo thioamide analog compound synthesis benzothiazole in water phase |
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