CN101463030A - Method for preparing anethol trithione - Google Patents
Method for preparing anethol trithione Download PDFInfo
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- CN101463030A CN101463030A CNA2009101108582A CN200910110858A CN101463030A CN 101463030 A CN101463030 A CN 101463030A CN A2009101108582 A CNA2009101108582 A CN A2009101108582A CN 200910110858 A CN200910110858 A CN 200910110858A CN 101463030 A CN101463030 A CN 101463030A
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Abstract
The invention discloses a preparation method of anethol trithione, relates to an organic compound, in particular to a method for preparing the anethol trithione by taking p-methoxy acetophenone and diethyl carbonate as raw materials to prepare p-methoxybenzoyl ethyl acetate under the action of alkali,and performing sulfur cyclization; and provides the preparation method of the anethol trithione with available and cheap raw materials, simple process, easy control, good product quality and high yield. The preparation method comprises the following steps: taking the p-methoxy acetophenone and the diethyl carbonate as the raw materials, and preparing a compound (I) ( the p-methoxybenzoyl ethyl acetate) by heating reaction under the action of the alkali; mixing the p-methoxybenzoyl ethyl acetate with phosphorus pentasulfide, sulfur, hexamethyldisiloxane and a solvent to obtain a mixture which is refluxed for reaction, and neutralized with potassium carbonate to obtain the product anethol trithione.
Description
Technical field
The present invention relates to a kind of organic compound, especially relating to a kind of employing p-methoxy-acetophenone and diethyl carbonate is that raw material makes under the alkali effect the methoxybenzoyl ethyl acetate, prepares the method for Anethol Trithione again through the sulphur cyclization.
Background technology
Nineteen forty-seven, Anethol Trithione was at first synthetic by German Battcher and Luttringhaus, and nineteen fifty French scientist Halpem and Gaudin have confirmed that Anethol Trithione has the effect that protects the liver with cholagogic.Afterwards, discover that Anethol Trithione had the effect of ptyalize and digestion promoting, first Application was in the treatment xerostomia in 1969.Up-to-date progress shows that Anethol Trithione very likely becomes the active drug of treatment lung cancer, and NIH etc. have all given to show great attention to the clinical trial of being correlated with.
The formal name used at school of Anethol Trithione is: 5-(right～p-methoxy-phenyl)-1,2-dithiacyclopentene-3-thioketones its chemical structural formula is for 5-(p-Methoxyphenyl)-3H-1,2-dithiole-3-thione}:
The synthetic method of relevant Anethol Trithione has been introduced following several route in the document.
1. (Lozac ' h, the Noel of synthetic route the earliest; Denis, Michel; Mollier, Yves; Sulfuration of organiccompounds.V.Sulfuration of propylbenzene derivatives, T.J.Bull.Soc.Chim.Fr., 1953:1016-1020) being that raw material and thiophosphoric anhydride carry out cyclization to anisole acetone under 210～220 ℃.
2.2000 (Thomas J.Curphey such as year Thomas J; Adam H.Libby; Dianions of 3-oxo dithioic acids:preparation and conversion to 3H-1,2-dithiole-3-thiones, Tetrahedron Lett., 2000,41,6977-6980.) to propose with the p-methoxy-acetophenone be that raw material and dithiocarbonic anhydride carry out cyclization, reaction scheme is:
3. in patent (PCT Int.Appl., 2006066894,29 Jun 2006), be raw material with the methyl allylphenol, its method is that methyl allylphenol and SULPHUR POWDER are heated to 200 ℃, and reaction 6h filters, ether wash the Anethol Trithione crude product, after re-crystallizing in ethyl acetate the Anethol Trithione finished product.
4, existing Anethol Trithione synthetic route is being to improve on the raw material with the methyl allylphenol, and its method is to add methyl allylphenol and dimethyl formamide in retort, stirs, and drops into SULPHUR POWDER, is heated to 146～150 ℃, insulation reaction 1.5h.After reaction finishes, be chilled to 80 ℃, the reclaim under reduced pressure dimethyl formamide is chilled to 66 ℃ with reaction mass, adds the dimethylbenzene gac, is heated to 108 ℃ and be incubated 0.5h, then filtered while hot.Filtrate is chilled to 0 ℃, and crystallization is filtered, wash crude product.After dimethylbenzene or butylacetate are refining the Anethol Trithione finished product, yield 40%.
In the above method, route 1 and 3 all exists high temperature vulcanized (200 ℃) reaction conditions, wayward on producing, and shortcoming such as energy consumption height; Though route 4 improves to some extent on the temperature of reaction of route 3, there is the cost recovery height in employed solvent dimethyl formamide boiling point height (153 ℃), shortcomings such as yield ability 40%; Route 2 has used the malodorous toxic reagent of dithiocarbonic anhydride, can cause in various degree actual bodily harm to operator in process of production.
Summary of the invention
The objective of the invention is at problem such as existing temperature of reaction height in the existing synthetic Anethol Trithione method, wayward and yield be low, provide a kind of raw material be easy to get inexpensive, technology is simple, easy to control.And the preparation method of the Anethol Trithione that the product quality that makes is good, yield is high.
Technical scheme of the present invention is to be raw material with p-methoxy-acetophenone and diethyl carbonate.
Synthetic route of the present invention is:
Comprise the steps:
1) be raw material with p-methoxy-acetophenone and diethyl carbonate, reacting by heating makes compound (I) under the alkali effect, promptly to the methoxybenzoyl ethyl acetate;
2) will be to methoxybenzoyl ethyl acetate and thiophosphoric anhydride, sulphur, hexamethyldisiloxane, solvent, the mixture back flow reaction is used the salt of wormwood neutralizing treatment, makes the product Anethol Trithione.
In step 1), the temperature of reacting by heating can be 40～110 ℃, and the time of reacting by heating is 1～4h, and described alkali is potassium tert.-butoxide, sodium hydride etc., and p-methoxy-acetophenone: diethyl carbonate: alkali is 1 in molar ratio: (3～5): (1～3).With p-methoxy-acetophenone and diethyl carbonate is raw material, and reacting by heating under the alkali effect can adopt following steps:
In reaction vessel, add toluene and diethyl carbonate, add alkali again, be warming up to 40～110 ℃, slowly add the p-methoxy-acetophenone toluene solution, react 1～4h after adding again, reaction solution is poured in the water after being cooled to room temperature, water layer extracts with toluene, merge organic layer, saturated nacl aqueous solution is washed, and organic layer is the toluene solution that contains the methoxybenzoyl ethyl acetate.
In step 2) in, described to the methoxybenzoyl ethyl acetate: thiophosphoric anhydride: sulphur: hexamethyldisiloxane is 1 in molar ratio: (1～2): (1～1.5): (3～5).Will be to methoxybenzoyl ethyl acetate and thiophosphoric anhydride, sulphur, hexamethyldisiloxane, solvent, the mixture back flow reaction is used the salt of wormwood neutralizing treatment, can adopt following steps:
In reaction vessel, add thiophosphoric anhydride, sulphur, toluene, hexamethyldisiloxane, mixture is warming up to backflow, add the toluene solution that contains the methoxybenzoyl ethyl acetate, reaction is to complete, and reaction solution cools off, add salt of wormwood, add entry again, add acetone, organic layer washs with solution of potassium carbonate, dilute sulphuric acid sodium solution, saturated nacl aqueous solution, organic layer is evaporated to dried, and getting solid through recrystallization is the product Anethol Trithione.
Compare with the preparation method of existing Anethol Trithione,, have the following advantages though the present invention adopts two-step synthetic method:
1, the present invention raw materials used inexpensive, be easy to get.
2, method reaction conditions gentleness of the present invention, temperature of reaction low (energy consumption is low), by product is few.
3,, total recovery can be increased to 60%～80% from 40%, thereby reduce cost significantly according to the inventive method.
Embodiment
The present invention is further illustrated for following examples.
Embodiment 1
(1) adds diethyl carbonate 48.0ml (0.4mol) and toluene in the 500ml reaction flask, add potassium tert.-butoxide 33.6g (0.3mol), be warming up to 80 ℃, slowly drip p-methoxy-acetophenone 15.0g (0.1mol) toluene solution.Add reaction 4h.Reaction finishes, and reduces to room temperature, pours in the water, tells organic layer, and water layer with toluene extraction once merges organic layer with saturated NaCl solution washing, and organic layer is the toluene solution that contains the methoxybenzoyl ethyl acetate.
(2) add thiophosphoric anhydride 26.68g (0.12mol), sulphur 4.8g (0.15mol), toluene, hexamethyldisiloxane 106.5ml (0.5mol) in the reaction flask, mixture is warming up to backflow.Slowly drip the toluene solution to the methoxybenzoyl ethyl acetate of above-mentioned preparation, drip off reaction to complete.The reaction solution cooling adds salt of wormwood 35.6g, slowly drips water 40ml, add acetone 100ml, organic layer washs with solution of potassium carbonate, dilute sulphuric acid sodium solution, saturated nacl aqueous solution, and organic layer is evaporated to dried, get the product Anethol Trithione through recrystallization, yield 70%, fusing point are 108～111 ℃.
Embodiment 2
(1) adds diethyl carbonate 48.0ml (0.4mol) and toluene in the 500ml reaction flask, add potassium tert.-butoxide 22.4g (0.2mol), be warming up to 110 ℃, slowly drip p-methoxy-acetophenone 15.0g (0.1mol) toluene solution.Add reaction 1h.Reaction finishes, and reduces to room temperature, pours in the water, tells organic layer, and water layer with toluene extraction once merges organic layer with saturated NaCl solution washing, and organic layer is the toluene solution that contains the methoxybenzoyl ethyl acetate.
(2) add thiophosphoric anhydride 22.2g (0.1mol), sulphur 4.8g (0.15mol), toluene, hexamethyldisiloxane 85.3ml (0.4mol) in the reaction flask, mixture is warming up to backflow.Slowly drip the toluene solution to the methoxybenzoyl ethyl acetate of above-mentioned preparation, drip off reaction to complete.The reaction liquid cooling adds salt of wormwood 35.6g, slowly drips water 40ml, add acetone 100ml, organic layer washs with solution of potassium carbonate, dilute sulphuric acid sodium solution, saturated nacl aqueous solution, and organic layer is evaporated to dried, get the product Anethol Trithione through recrystallization, yield 64%, fusing point are 108～111 ℃.
Embodiment 3
(1) adds toluene in the reaction flask, slowly add sodium hydride (content 60%) 7.2g, diethyl carbonate 60.0ml (0.5mol) under stirring, be warming up to 40 degree, slowly drip p-methoxy-acetophenone 15.0g (0.1mol) toluene solution.Add reaction 4h.Reaction finishes, and reaction solution is poured in the frozen water, transfers pH=9.0 with dense HCl.Water layer extracts with toluene, and with sodium hydrogen carbonate solution washing, saturated NaCl solution washing, organic layer is the toluene solution that contains the methoxybenzoyl ethyl acetate.
(2) electronic being stirred in adds thiophosphoric anhydride 44.4g (0.2mol), sulphur 3.2g (0.1mol), dimethylbenzene, hexamethyldisiloxane 63.3ml (0.3mol) in the 500ml reaction flask, and mixture is warming up to backflow.Slowly drip to above-mentioned preparation to methoxybenzoyl ethyl acetate (about 0.1mol) toluene solution, drip off reaction to fully.The reaction solution cooling adds salt of wormwood 35.6g (0.1mol), slowly drips water 40ml, add acetone 100ml, organic layer washs with solution of potassium carbonate, dilute sulphuric acid sodium solution, saturated nacl aqueous solution, and organic layer is evaporated to dried, get the product Anethol Trithione through recrystallization, yield 80%.
Embodiment 4
(1) adds toluene in the reaction flask, slowly add sodium hydride (content 60%) 4g, diethyl carbonate 36.0ml (0.3mol) under stirring, be warming up to 60 degree, slowly drip p-methoxy-acetophenone 15.0g (about 0.1mol) toluene solution.Add reaction 4h.Reaction finishes, and reaction solution is poured in the frozen water, transfers pH=9.0 with dense HCl.Water layer extracts with toluene, and with sodium hydrogen carbonate solution washing, saturated NaCl solution washing, organic layer is the toluene solution that contains the methoxybenzoyl ethyl acetate.
(2) electronic being stirred in adds thiophosphoric anhydride 26.68g (0.12mol), sulphur 3.2g (0.1mol), dimethylbenzene 200ml, hexamethyldisiloxane 74.6ml (0.35mol) in the 500ml reaction flask, and mixture is warming up to backflow.Slowly drip methoxybenzoyl ethyl acetate (about 0.1mol) toluene solution, drip off reaction to complete to above-mentioned preparation.The reaction solution cooling adds salt of wormwood 35.6g (0.1mol), slowly drips water 40ml, add acetone 100ml, organic layer is with solution of potassium carbonate, dilute sulphuric acid sodium solution, saturated nacl aqueous solution washing, the organic layer dried over sodium sulfate, and filtration, organic layer are evaporated to dried product Anethol Trithione.
Claims (8)
1. the preparation method of Anethol Trithione is characterized in that its synthetic route is:
2. the preparation method of Anethol Trithione as claimed in claim 1 is characterized in that comprising the steps:
1) be raw material with p-methoxy-acetophenone and diethyl carbonate, reacting by heating makes compound (I) under the alkali effect, promptly to the methoxybenzoyl ethyl acetate;
2) will be to methoxybenzoyl ethyl acetate and thiophosphoric anhydride, sulphur, hexamethyldisiloxane, solvent, the mixture back flow reaction is used the salt of wormwood neutralizing treatment, makes the product Anethol Trithione.
3. the preparation method of Anethol Trithione as claimed in claim 2 is characterized in that in step 1), and the temperature of reacting by heating is 40～110 ℃, and the time of reacting by heating is 1～4h.
4. the preparation method of Anethol Trithione as claimed in claim 2 is characterized in that in step 1), and described alkali is potassium tert.-butoxide, sodium hydride.
5. the preparation method of Anethol Trithione as claimed in claim 2 is characterized in that in step 1), and in molar ratio, p-methoxy-acetophenone: diethyl carbonate: alkali is 1: 3～5: 1～3.
6. the preparation method of Anethol Trithione as claimed in claim 2 is characterized in that in step 1), is raw material with p-methoxy-acetophenone and diethyl carbonate, and the concrete steps of reacting by heating are under the alkali effect:
In reaction vessel, add toluene and diethyl carbonate, add alkali again, be warming up to 40～110 ℃, slowly add the p-methoxy-acetophenone toluene solution, react 1～4h after adding again, reaction solution is poured in the water after being cooled to room temperature, water layer extracts with toluene, merge organic layer, saturated nacl aqueous solution is washed, and organic layer is the toluene solution that contains the methoxybenzoyl ethyl acetate.
7. the preparation method of Anethol Trithione as claimed in claim 2 is characterized in that in step 2) in, described to the methoxybenzoyl ethyl acetate: thiophosphoric anhydride: sulphur: hexamethyldisiloxane is 1: 1～2: 1～1.5: 3～5 in molar ratio.
8. the preparation method of Anethol Trithione as claimed in claim 2, it is characterized in that in step 2) in, will be to methoxybenzoyl ethyl acetate and thiophosphoric anhydride, sulphur, hexamethyldisiloxane, solvent, the mixture back flow reaction with the concrete steps of salt of wormwood neutralizing treatment is:
In reaction vessel, add thiophosphoric anhydride, sulphur, toluene, hexamethyldisiloxane, mixture is warming up to backflow, add the toluene solution that contains the methoxybenzoyl ethyl acetate, reaction is to complete, and reaction solution cools off, add salt of wormwood, add entry again, add acetone, organic layer washs with solution of potassium carbonate, dilute sulphuric acid sodium solution, saturated nacl aqueous solution, organic layer is evaporated to dried, and getting solid through recrystallization is the product Anethol Trithione.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993166A (en) * | 2012-12-13 | 2013-03-27 | 苏州大学 | Preparation method and application of 3H-1,2-dithiole-3-thioketone compound |
| CN103524482A (en) * | 2013-09-22 | 2014-01-22 | 黄冈赛康药业有限公司 | Preparation method of anethol trithione |
| CN104031016A (en) * | 2014-06-24 | 2014-09-10 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of apigenin |
| CN106334471A (en) * | 2016-09-27 | 2017-01-18 | 东莞市联洲知识产权运营管理有限公司 | Medicinal powder stirrer with rotary overturning function |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3847943A (en) * | 1972-09-08 | 1974-11-12 | P Warner | Preparing anethole trithione using sulfolane solvent |
| EP0343303A1 (en) * | 1988-05-27 | 1989-11-29 | Kali-Chemie Pharma GmbH | Medicines containing 1,2-dithiol-3-thion-S-oxide compounds |
| AU2003202763A1 (en) * | 2002-02-13 | 2003-09-04 | Solvay Pharma | Use of anethole dithiolethione in lung cancer chemoprevention |
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2009
- 2009-01-09 CN CN2009101108582A patent/CN101463030B/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993166A (en) * | 2012-12-13 | 2013-03-27 | 苏州大学 | Preparation method and application of 3H-1,2-dithiole-3-thioketone compound |
| CN103524482A (en) * | 2013-09-22 | 2014-01-22 | 黄冈赛康药业有限公司 | Preparation method of anethol trithione |
| CN104031016A (en) * | 2014-06-24 | 2014-09-10 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of apigenin |
| CN106334471A (en) * | 2016-09-27 | 2017-01-18 | 东莞市联洲知识产权运营管理有限公司 | Medicinal powder stirrer with rotary overturning function |
| CN106334471B (en) * | 2016-09-27 | 2019-01-29 | 湖南神舟医药有限公司 | A kind of medicine power stirrer seething function with rotation |
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| CN101463030B (en) | 2012-03-21 |
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