CN1446811A - Method for preparing 2-trifluoromethyl-10-oxaneones - Google Patents
Method for preparing 2-trifluoromethyl-10-oxaneones Download PDFInfo
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- CN1446811A CN1446811A CN 03115623 CN03115623A CN1446811A CN 1446811 A CN1446811 A CN 1446811A CN 03115623 CN03115623 CN 03115623 CN 03115623 A CN03115623 A CN 03115623A CN 1446811 A CN1446811 A CN 1446811A
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Abstract
A process for preparing 2-trifluoromethyl-10-oxanone from p-trifluorotoluene and o-mercaptobenzoic acid includes nucleophilic substitution reaction on aryl ring to obtain diaryl thioether, and cyclization reaction with concentrated sulfuric acid. Its advantage is short period.
Description
Technical field
The present invention relates to the synthetic method of 2-Trifluoromethyl-1 0-oxane ketone
Technical background
2-Trifluoromethyl-1 0-oxane ketone is a kind of important medicine intermediate, also is the important intermediate of preparation antidepressant flupenthixol, and its structural formula is as follows:
United States Patent (USP) (US925539) has reported that with p-chloro benzo trifluoride-99 and o-mercaptobenzoic acid be raw material, the method for preparing 2-Trifluoromethyl-1 0-oxane ketone through polystep reaction: p-chloro benzo trifluoride-99 with mixed acid nitrification after, generate 3-nitro-4-chlorobenzotrifluoride, this compound and o-mercaptobenzoic acid reaction generate 2-(4-trifluoromethyl-2-nitro) benzene Thiosalicylic acid, be reduced into corresponding amine through tin protochloride then, this amine obtains intermediate 2-(4-trifluoromethyl) benzene Thiosalicylic acid after diazotization is taken off the amido reaction, this compound obtains 2-Trifluoromethyl-1 0-oxane ketone through the sulfuric acid cyclisation.The synthetic route of this method intermediate is tediously long, and overall yield of reaction is low, the cost height.
United States Patent (USP) (US4101558) has been reported the method for preparing 2 replacement De oxane ketone: o-mercaptobenzoic acid and chlorine reaction generate adjacent chlorine sulfydryl Benzoyl chloride, generate 2 replacement De oxane ketone with single-substituted reaction again.The shortcoming of this method is that the use existence of chlorine jeopardizes safe problem, and equipment corrosion is big, and industrial equipment requires high.
For synthesizing of intermediate diphenyl sulfide formic acid, except that above-mentioned United States Patent (USP) reported method, German Patent (DE3723079) has reported that with 0-chloro-benzoic acid and thiophenol be the synthetic method of raw material, the shortcoming of this method is with lithium hydroxide as acid binding agent, naphthane is as solvent, the reaction cost height.Coll.Czen.chem.commun. (vol.44, pgs.2124-2138,1979) reported method be the chlorinated benzene formic acid that replaces with nitro with the thiophenol reaction after reduce, diazotization desamination reaction and making.There is identical shortcoming with US 925539 reported method.
Summary of the invention
The technical issues that need to address of the present invention are the preparation methods that disclose a kind of 2-Trifluoromethyl-1 0-oxane ketone, to overcome the defective that the prior art problem exists.
The present invention is a raw material with p-chloro benzo trifluoride-99 and o-mercaptobenzoic acid, and nucleophilic substitution reaction synthesis of diaryl thioether on aromatic ring has made target compound through vitriol oil cyclisation two-step reaction again.Preparation method of the present invention comprises the steps:
(1) be that raw material, aprotic polar solvent are solvent with o-mercaptobenzoic acid and p-chloro benzo trifluoride-99, preferred solvent is N, dinethylformamide, dimethyl sulfoxide (DMSO) or tetramethylene sulfone, in the presence of acid binding agent, get compound 2-(4-phenylfluoroform) Thiosalicylic acid after back flow reaction 16-22 hour; Wherein: the mol ratio of reactant is an o-mercaptobenzoic acid: p-chloro benzo trifluoride-99: acid binding agent=1: 1-5: 2--6, described acid binding agent are alkali metal hydroxide or alkaline carbonate.
(2) will be by 2-(the 4-phenylfluoroform sulfydryl) phenylformic acid of step (1) gained and the vitriol oil back flow reaction 2-4 hour, after filtration, must target product 2-Trifluoromethyl-1 0-oxane ketone after washing and the drying.Wherein: the mol ratio of 2-(the 4-phenylfluoroform sulfydryl) phenylformic acid and the vitriol oil is 1: 15-25.
Reaction equation of the present invention is as follows:
This method has shortened operational path, uses raw material cheap and easy to get, greatly reduces production cost; Operation is simple, and the reaction conditions gentleness can realize suitability for industrialized production.
Embodiment
For better understanding the present invention, the invention will be further described below by embodiment, but it does not influence protection scope of the present invention:
Embodiment 1
O-mercaptobenzoic acid 20g (0.13mol), sodium hydroxide 12g (0.3mol), DMF120ml, p-chloro benzo trifluoride-99 32g (0.177mol) are warmed up to backflow, reacted 20 hours, cool to room temperature is poured in the 300ml water, adds 1M hydrochloric acid, regulate PH=2-3, suction filtration, filter cake washs with less water, the dry solid 34g that gets, yield 87%, m.p.138-144 ℃.
2-(4-phenylfluoroform sulfydryl) phenylformic acid 6g (0.02mol), vitriol oil 20ml is warmed up to backflow, reacted 2 hours, cool to room temperature is slowly poured in the 120ml water, suction filtration, filter cake are dissolved in the 180ml trichloromethane, and neutralizing to diluted sodium hydroxide solution is alkalescence, separatory, the oil-reservoir water washing is to neutrality, anhydrous magnesium sulfate drying, steam and remove trichloromethane, remaining solid sherwood oil recrystallization gets faint yellow solid 3.2g, yield 56.7%, m.p.143-146 ℃, HPLC content 99.1%.
Embodiment 2
O-mercaptobenzoic acid 20g (0.13mol), potassium hydroxide 28g (0.5mol), DMSO120ml, p-chloro benzo trifluoride-99 47.0g (0.26mol), be warmed up to backflow, reacted cool to room temperature 24 hours, pour in the 300mL water, add 1M hydrochloric acid, regulate PH2-3, suction filtration, filter cake washs with less water, dry solid 31.2g, yield 80.0%, m.p.136-144 ℃ of getting.
2-(4-phenylfluoroform sulfydryl) phenylformic acid 6g (0.02mol), vitriol oil 24mL is warmed up to backflow, reacted 4 hours, cool to room temperature slowly adds in the 120ml water, suction filtration, filter cake are dispersed in the 180ml water, and neutralizing to diluted sodium hydroxide solution is alkalescence, filter, filter cake washes with water, drying, use the sherwood oil recrystallization, get faint yellow solid 2.6g, yield 46%, m.p.143-146 ℃.
Claims (4)
1, a kind of method for preparing 2-Trifluoromethyl-1 0-oxane ketone is characterized in that described preparation method comprises the steps:
(1) is that raw material, aprotic polar solvent are solvent with o-mercaptobenzoic acid and p-chloro benzo trifluoride-99, in the presence of acid binding agent, gets compound 2-(4-phenylfluoroform) Thiosalicylic acid after back flow reaction 16-22 hour;
(2) with 2-(4-phenylfluoroform sulfydryl) phenylformic acid and the vitriol oil back flow reaction 2-4 hour, cyclisation generated target product 2-Trifluoromethyl-1 0-oxane ketone;
Wherein: the mol ratio of reactant is, o-mercaptobenzoic acid: p-chloro benzo trifluoride-99: acid binding agent=1: 1-5: 2-6, described acid binding agent is alkali metal hydroxide or alkaline carbonate, and the mol ratio of 2-(the 4-phenylfluoroform sulfydryl) phenylformic acid and the vitriol oil is 1: 15-25.
2, the method for claim 1 is characterized in that, wherein said acid binding agent is sodium hydroxide or potassium hydroxide.
3, the method for claim 1 is characterized in that, the solvent in the step (1) is N, dinethylformamide, dimethyl sulfoxide (DMSO) or tetramethylene sulfone.
4, method as claimed in claim 2 is characterized in that, the solvent in the step (1) is N, dinethylformamide, dimethyl sulfoxide (DMSO).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031156231A CN100355747C (en) | 2003-03-03 | 2003-03-03 | Method for preparing 2-trifluoromethyl-10-oxaneones |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB031156231A CN100355747C (en) | 2003-03-03 | 2003-03-03 | Method for preparing 2-trifluoromethyl-10-oxaneones |
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| CN1446811A true CN1446811A (en) | 2003-10-08 |
| CN100355747C CN100355747C (en) | 2007-12-19 |
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| CNB031156231A Expired - Fee Related CN100355747C (en) | 2003-03-03 | 2003-03-03 | Method for preparing 2-trifluoromethyl-10-oxaneones |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321069A (en) * | 2011-08-09 | 2012-01-18 | 济南富创医药科技有限公司 | Preparation method of 2-trifluoromethylthioxanthone |
| CN107176916A (en) * | 2016-03-09 | 2017-09-19 | 江苏同禾药业有限公司 | A kind of 2-（To TRIFLUOROMETHYLPHENYLTHIO）The preparation method of benzoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB9113580D0 (en) * | 1991-06-24 | 1991-08-14 | Int Bio Synthetics Ltd | Thioxanthone derivatives |
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2003
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321069A (en) * | 2011-08-09 | 2012-01-18 | 济南富创医药科技有限公司 | Preparation method of 2-trifluoromethylthioxanthone |
| CN102321069B (en) * | 2011-08-09 | 2013-03-20 | 济南富创医药科技有限公司 | Preparation method of 2-trifluoromethylthioxanthone |
| CN107176916A (en) * | 2016-03-09 | 2017-09-19 | 江苏同禾药业有限公司 | A kind of 2-（To TRIFLUOROMETHYLPHENYLTHIO）The preparation method of benzoic acid |
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| CN100355747C (en) | 2007-12-19 |
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Granted publication date: 20071219 Termination date: 20120303 |