CN1228324C - 2,5-dimethyl-4-[2,-fluorosulphuric radical]-benzoethylamine and its preparation and uses - Google Patents
2,5-dimethyl-4-[2,-fluorosulphuric radical]-benzoethylamine and its preparation and uses Download PDFInfo
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- CN1228324C CN1228324C CN 03128052 CN03128052A CN1228324C CN 1228324 C CN1228324 C CN 1228324C CN 03128052 CN03128052 CN 03128052 CN 03128052 A CN03128052 A CN 03128052A CN 1228324 C CN1228324 C CN 1228324C
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- dimethoxy
- ethylmercapto group
- fluorine ethylmercapto
- ether
- terephthaldehyde
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Abstract
The present invention relates to 2, 5-dimethoxy-4-[2'-fluoroethylthio]-phenylethylamine whose structural formula is disclosed by the right expression. The present invention also provides a preparation method of the compound. In the preparation method, under an acid condition, 2, 5-dimethoxy benzenesulfonyl chloride is reduced by zinc powder, and a reduced product is distilled in a decompressing mode and is condensed with 1-fluoro-2-bromethyl in an alkali methanol solution. 2-[2'-fluoroethylthio]p-phenyldimethyl ether obtained by water dilution, methylene chloride extraction and decompressing distillation reacts with phosphorus oxychloride and dimethyl formamide, the obtained product and nitromethane are condensed, and the final product of the 2, 5-dimethoxy-4-[2'-fluoroethylthio]-phenylethylamine is obtained by the reduction of lithium aluminum hydride in tetrahydrofuran. The 2, 5-dimethoxy-4-[2'-fluoroethylthio]-phenylethylamine can be used as an intermediate of a medicament, particularly the intermediate of a medicament for treating neurogenic diseases.
Description
Technical field
The present invention relates to-kinds 2, the method for making of 5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenylethylamine.
Background technology
People find that for a long time for some physiologically active substance, if import fluorine atom to its a certain key position, its activity just amazing variation might take place.At present, in the research of former medicine of exploitation and plant protection product, the importing of fluorine has been considered to a kind of important means.As a kind of new compound, 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenylethylamine and synthetic method thereof are not seen bibliographical information as yet.
Summary of the invention
Task of the present invention provides a kind of new compound 2, the method for making of 5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenylethylamine.
Technical scheme provided by the invention is: 2, and 5-dimethoxy～4-[2 '-fluorine ethylmercapto group]-phenylethylamine, its structural formula is
The method for making of above-claimed cpd is 70～80., under the acidic conditions (pH＜1), 2,5-dimethoxy benzene sulfonyl chloride is through zinc powder reduction, underpressure distillation then obtains 2-sulfydryl terephthaldehyde ether; 2-sulfydryl terephthaldehyde ether in 60～80 ℃, the methanol solution of alkalescence with the condensation of 1-fluoro-2-monobromethane, through water release, dichloromethane extraction, underpressure distillation obtain 2-[2 '-fluorine ethylmercapto group] terephthaldehyde's ether; 2-[2 '-fluorine ethylmercapto group] terephthaldehyde's ether and phosphorus oxychloride and dimethyl formamide react under 60～80 ℃ of conditions and obtain 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenyl aldehyde, gained 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenyl aldehyde obtains 2 with Nitromethane 99Min. 90～100 ℃ of condensations again, 5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-beta-nitrostyrene; With 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-beta-nitrostyrene in tetrahydrofuran (THF), under 0～50 ℃, acidic conditions (pH＜1) with lithium aluminium hydride reduce 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenylethylamine.
2,5-dimethoxy benzene sulfonyl chloride can make by following method, and methylene dichloride and terephthaldehyde's ether are mixed stirring and dissolving, be cooled to 0～10 ℃ of following agitation and dropping chlorsulfonic acid and sulfur oxychloride, tell lower floor's oil reservoir, to its distill yellow solid 2,5-dimethoxy benzene sulfonyl chloride.
The reaction equation of said process is as follows:
2 of the present invention's preparation, 5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenylethylamine can be used as highly active pharmaceutical intermediate because its activity of importing of fluorine strengthens greatly, especially for the pharmaceutical intermediate of treatment nervous system disease.
Embodiment
In the 250ml there-necked flask, add 105ml methylene dichloride, 13.5g terephthaldehyde ether, stirring and dissolving, ice bath cooling (0～10 ℃), stir and drip 26.5ml chlorsulfonic acid and 10ml sulfur oxychloride down, reacted 2 hours, and with in its impouring 280ml frozen water, told lower floor's oil reservoir under stirring, steam and remove methylene dichloride (recovery), get yellow solid 2,5-dimethoxy benzene sulfonyl chloride, oven-dried weight 19.8g, productive rate 85%, fusing point 115-117 ℃.
In the 500ml there-necked flask, add the 68ml water and the 23ml vitriol oil, when treating that temperature drops to about 70 ℃, adding 12g2,5-dimethoxy benzene sulfonyl chloride and 18g zinc powder reacted 1 hour down at 80 ℃, and filtration, decompression, steaming are slipped and are obtained 8.2g 2-sulfydryl terephthaldehyde ether.
In the 250ml there-necked flask, add 100ml methyl alcohol, 6.9 gram potassium hydroxide is preheating to 50～60 ℃, add 13.0g 2-sulfydryl terephthaldehyde's ether and 9.6g1-fluoro-2-monobromethane successively, reflux (about 70 ℃) 2 hours, then reaction solution is under agitation poured in the 1000ml water, with 100ml dichloromethane extraction three times, extraction liquid merges, with the sodium hydroxide washing of 5% (weight percent), after steaming desolventizes, underpressure distillation, collect the cut of 150 ℃/2mmHg, get colourless transparent liquid 2-[2 '-fluorine ethylmercapto group] terephthaldehyde's ether 16.0g, productive rate 97%, content 〉=98%.
Toward 13.4 gram N, add 26.8 gram phosphorus oxychloride in the dinethylformamide, heated 10 minutes down at 60 ℃, add 16.8 gram 2-[2 '-fluorine ethylmercapto groups again] terephthaldehyde's ether, 70 ℃ of stirring reactions 1 hour, reaction solution poured in 1.5 liters 55 ℃ the warm water, 15.1 gram yellow solids 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenyl aldehyde.
In 80 gram Nitromethane 99Min.s, add 15 grams 2 successively, 5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenyl aldehyde and 1.4 gram anhydrous acetic acid ammoniums are heated to 95 ℃ of reactions 2 hours, and steaming desolventizes, get 12 gram garnet solids 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-beta-nitrostyrene.
Under the ice bath cooling, in the 132ml tetrahydrofuran (THF), add the 3g lithium aluminium hydride, splash into 2.1ml 100% sulfuric acid under stirring, add 5.02 grams 2 again, 5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-beta-nitrostyrene, backflow 2h, the aqueous sodium hydroxide solution that adds 8.5 milliliters of Virahols and 8.5 milliliter 15% after the cooling again, filter, filter residue washs with tetrahydrofuran (THF), filtrate and washing lotion merge the cut that the back steaming desolventizes, 155-160 ℃/0.4mmHg is collected in underpressure distillation, obtain 3.0g colourless oil liquid 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenylethylamine.Analyze content 〉=98% through HPLC.
Claims (2)
1.2 the method for making of 5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenylethylamine is characterized in that: under 70～80 ℃, the condition of pH＜1,2,5-dimethoxy benzene sulfonyl chloride is through zinc powder reduction, and underpressure distillation then obtains 2-sulfydryl terephthaldehyde ether; 2-sulfydryl terephthaldehyde ether in 60～80 ℃, the methanol solution of alkalescence with the condensation of 1-fluoro-2-monobromethane, through water release, dichloromethane extraction, underpressure distillation obtain 2-[2 '-fluorine ethylmercapto group] terephthaldehyde's ether; 2-[2 '-fluorine ethylmercapto group] terephthaldehyde's ether and phosphorus oxychloride and dimethyl formamide react under 60～80 ℃ of conditions and obtain 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenyl aldehyde, gained 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenyl aldehyde obtains 2 with Nitromethane 99Min. 90～100 ℃ of condensations again, 5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-beta-nitrostyrene; With 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-beta-nitrostyrene in tetrahydrofuran (THF), under 0～50 ℃, the condition of pH＜1 with lithium aluminium hydride reduce 2,5-dimethoxy-4 '-[2 '-fluorine ethylmercapto group]-phenylethylamine.
2. method for making according to claim 1, it is characterized in that: 2,5-dimethoxy benzene sulfonyl chloride makes by following method, methylene dichloride and terephthaldehyde's ether are mixed stirring and dissolving, be cooled to 0～10 ℃ of following agitation and dropping chlorsulfonic acid and sulfur oxychloride, tell lower floor's oil reservoir, to its distill 2,5-dimethoxy benzene sulfonyl chloride.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 03128052 CN1228324C (en) | 2003-05-28 | 2003-05-28 | 2,5-dimethyl-4-[2,-fluorosulphuric radical]-benzoethylamine and its preparation and uses |
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| CN 03128052 CN1228324C (en) | 2003-05-28 | 2003-05-28 | 2,5-dimethyl-4-[2,-fluorosulphuric radical]-benzoethylamine and its preparation and uses |
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| CN1456552A CN1456552A (en) | 2003-11-19 |
| CN1228324C true CN1228324C (en) | 2005-11-23 |
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