CN108238864A - The synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxys) -2- acetone - Google Patents
The synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxys) -2- acetone Download PDFInfo
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- CN108238864A CN108238864A CN201710482856.0A CN201710482856A CN108238864A CN 108238864 A CN108238864 A CN 108238864A CN 201710482856 A CN201710482856 A CN 201710482856A CN 108238864 A CN108238864 A CN 108238864A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
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Abstract
The invention discloses the synthetic methods of antiarrhythmic drug intermediate 1 (2,6 dimethoxy) 2 acetone, include the following steps：1 (2,6 dimethyl, 3 hydroxyphenoxy) 2 aminopropanes are added in reaction vessel, potassium nitrate solution controls mixing speed, increases solution temperature, adds in BBP(Butyl Benzyl Phthalate solution, the reaction was continued；Dicyclopentadienyl vanadium dichloride is added in, metabisulfite solution reduces temperature, stands, solution is layered, and is separated oil reservoir, is washed with sulfur hexafluoride solution, the washing of 2 chlorobenzene phenol solutions, it is recrystallized in chloromethanes solution, dehydrating agent dehydration obtains finished product 1 (2,6 dimethoxy) 2 acetone.
Description
Technical field
The present invention relates to a kind of preparation methods of medicine intermediate, belong to organic synthesis field more particularly to the anti-rhythm of the heart loses
The synthetic method of normal pharmaceutical intermediate 1- (2,6- dimethoxys) -2- acetone.
Background technology
1- (2,6- dimethoxys) -2- acetone is mainly as the centre of antiarrhythmic drug and mexiletine pharmaceutical synthesis
Body.Existing synthetic method is mostly using 2,6- xylenols hydroxypropylation, life under sodium hydroxide effect with propylene oxide
Into (2,6- dimethyl phenoxy) isopropanol, the product are made with sulfuric acid and sodium dichromate oxidation in the latter.Since the synthetic method needs
Wanting sulfuric acid and sodium dichromate, danger coefficient is higher during the reaction for sulfuric acid solution, and sodium dichromate solution is to ring as reactant
Border pollution is larger, and technics comparing is complicated, it is therefore necessary to propose a kind of new synthetic method.
Invention content
Technical problems based on background technology, the present invention propose antiarrhythmic drug intermediate 1- (2,6- bis-
Methoxyl group) -2- acetone synthetic method, include the following steps：
A, 1- (2,6- dimethyl -3- Hydroxy-phenoxies) -2- aminopropanes are added in reaction vessel, 2L potassium nitrate is molten
Liquid, controls mixing speed 250-270rpm, and raising solution temperature reacts 60-90min to 35-42 DEG C, adds in phthalic acid fourth
Benzyl ester solution, the reaction was continued 30-50min；
B, dicyclopentadienyl vanadium dichloride is added in, 1.3L metabisulfite solutions react 60-80min, reduce temperature to 10-14 DEG C, quiet
30-40min is put, solution layering separates oil reservoir, washed with sulfur hexafluoride solution, 2- chlorobenzenes phenol solution washing, in chloromethanes solution
Middle recrystallization, dehydrating agent dehydration, obtains finished product 1- (2,6- dimethoxy) -2- acetone.
Preferably, potassium nitrate solution mass fraction is 15-22%.
Preferably, BBP(Butyl Benzyl Phthalate liquid quality fraction is 40-55%.
Preferably, metabisulfite solution mass fraction is 20-26%.
Preferably, sulfur hexafluoride liquid quality fraction is 50-56%.
Preferably, 2- chlorophenols liquid quality fraction is 65-72%.
Preferably, chloromethanes liquid quality fraction is 80-87%.
Entire reaction process can be represented with following reaction formula：
Compared to synthetic method disclosed in background technology, antiarrhythmic drug intermediate 1- (2,6- provided by the invention
Dimethoxy) -2- acetone synthetic method, which does not need to sulfuric acid and sodium dichromate as reactant, avoids sulphur
Environmental pollution caused by reaction process danger coefficient raising caused by acid solution and sodium dichromate solution, reacts intermediate link
Reduce very much, the reaction time also shortens much, and reaction yield also improves, while the present invention provides a kind of new synthesis roads
Line is laid a good foundation further to promote reaction yield.
Specific embodiment
Embodiment 1：
The synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxy) -2- acetone, includes the following steps：
A, 1- (2,6- dimethyl -3- Hydroxy-phenoxies) -2- aminopropanes of 2mol, 2L matter are added in reaction vessel
The potassium nitrate solution that score is 15% is measured, controls mixing speed 250rpm, raising solution temperature reacts 60min to 35 DEG C, adds in
The mass fraction of 3mol is 40% BBP(Butyl Benzyl Phthalate solution, the reaction was continued 30min；
B, the dicyclopentadienyl vanadium dichloride of 2mol is added in, 1.3L mass fractions are 20% metabisulfite solution, react 60min,
Temperature is reduced to 10 DEG C, stands 30min, solution layering separates oil reservoir, is washed with the sulfur hexafluoride solution that mass fraction is 50%
It washs, the 2- chlorobenzenes phenol solution that mass fraction is 65% washs, and is recrystallized in mass fraction is 80% chloromethanes solution, anhydrous sulphur
Sour magnesium dehydrating agent dehydration, obtains finished product 1- (2,6- dimethoxy) -2- acetone 323.96, yield 91%.
Embodiment 2：
The synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxy) -2- acetone, includes the following steps：
A, 1- (2,6- dimethyl -3- Hydroxy-phenoxies) -2- aminopropanes of 2mol, 2L matter are added in reaction vessel
The potassium nitrate solution that score is 15% is measured, controls mixing speed 260rpm, raising solution temperature reacts 80min to 37 DEG C, adds in
The mass fraction of 3.5mol is 47% BBP(Butyl Benzyl Phthalate solution, the reaction was continued 40min；
B, the dicyclopentadienyl vanadium dichloride of 2.5mol is added in, 1.3L mass fractions are 23% metabisulfite solution, are reacted
70min reduces temperature to 12 DEG C, stands 35min, and solution layering separates oil reservoir, molten with the sulfur hexafluoride that mass fraction is 53%
Liquid washs, and the 2- chlorobenzenes phenol solution that mass fraction is 68% washs, and is recrystallized in the chloromethanes solution for being 83% in mass fraction,
Anhydrous magnesium sulfate dehydrating agent is dehydrated, and obtains finished product 1- (2,6- dimethoxy) -2- acetone 331.08g, yield 93%.
Embodiment 3：
The synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxy) -2- acetone, includes the following steps：
A, 1- (2,6- dimethyl -3- Hydroxy-phenoxies) -2- aminopropanes of 2mol, 2L matter are added in reaction vessel
Amount score is 22% potassium nitrate solution, controls mixing speed 270rpm, and raising solution temperature reacts 90min to 42 DEG C, adds in
4mol mass fractions are 55% BBP(Butyl Benzyl Phthalate solution, the reaction was continued 50min；
B, the dicyclopentadienyl vanadium dichloride of 3mol is added in, 1.3L mass fractions are 26% metabisulfite solution, react 80min, drop
Low temperature stands 40min to 14 DEG C, and solution layering separates oil reservoir, is washed with the sulfur hexafluoride solution that mass fraction is 56%,
The 2- chlorobenzenes phenol solution washing of mass fraction 72%, recrystallizes, Carbon Dioxide in chloromethanes solution of the mass fraction for 87%
Potassium dehydrating agent is dehydrated, and obtains finished product 1- (2,6- dimethoxy) -2- acetone 341.76g, yield 96%.
It described in above example, is merely preferred embodiments of the present invention, but protection scope of the present invention not office
Be limited to this, any one skilled in the art in the technical scope disclosed by the present invention, the technique according to the invention
Scheme and its inventive concept are subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (8)
- The synthetic method of antiarrhythmic drug intermediate 1- 1. (2,6- dimethoxy) -2- acetone, which is characterized in that including such as Lower step：A, 1- (2,6- dimethyl -3- Hydroxy-phenoxies) -2- aminopropanes, 2L potassium nitrate solutions, control are added in reaction vessel Mixing speed 250-270rpm processed, raising solution temperature react 60-90min to 35-42 DEG C, add in BBP(Butyl Benzyl Phthalate Solution, the reaction was continued 30-50min；B, dicyclopentadienyl vanadium dichloride is added in, 1.3L metabisulfite solutions react 60-80min, reduce temperature to 10-14 DEG C, stand 30-40min, solution layering, separates oil reservoir, is washed with sulfur hexafluoride solution, 2- chlorobenzenes phenol solution washing, in chloromethanes solution Recrystallization, dehydrating agent dehydration, obtains finished product 1- (2,6- dimethoxy) -2- acetone.
- 2. the synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxy) -2- acetone according to claim 1, It is characterized in that, the potassium nitrate solution mass fraction is 15-22%.
- 3. the synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxy) -2- acetone according to claim 1, It is characterized in that, the BBP(Butyl Benzyl Phthalate liquid quality fraction is 40-55%.
- 4. the synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxy) -2- acetone according to claim 1, It is characterized in that, the metabisulfite solution mass fraction is 20-26%.
- 5. the synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxy) -2- acetone according to claim 1, It is characterized in that, the sulfur hexafluoride liquid quality fraction is 50-56%.
- 6. the synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxy) -2- acetone according to claim 1, It is characterized in that, the 2- chlorophenols liquid quality fraction is 65-72%.
- 7. the synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxy) -2- acetone according to claim 1, It is characterized in that, the chloromethanes liquid quality fraction is 80-87%.
- 8. the synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxy) -2- acetone according to claim 1, It is characterised in that it includes following steps：A, 1- (2,6- dimethyl -3- Hydroxy-phenoxies) -2- aminopropanes of 2mol, 2L mass point are added in reaction vessel Number is 22% potassium nitrate solution, controls mixing speed 270rpm, and raising solution temperature reacts 90min to 42 DEG C, adds in 4mol matter Measure the BBP(Butyl Benzyl Phthalate solution that score is 55%, the reaction was continued 50min；B, the dicyclopentadienyl vanadium dichloride of 3mol is added in, 1.3L mass fractions are 26% metabisulfite solution, react 80min, reduce temperature Degree stands 40min to 14 DEG C, and solution layering separates oil reservoir, is washed with the sulfur hexafluoride solution that mass fraction is 56%, quality The 2- chlorobenzenes phenol solution washing of score 72%, recrystallizes, Anhydrous potassium carbonate takes off in chloromethanes solution of the mass fraction for 87% Aqua is dehydrated, and obtains finished product 1- (2,6- dimethoxy) -2- acetone.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710482856.0A CN108238864A (en) | 2017-06-22 | 2017-06-22 | The synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxys) -2- acetone |
| GBGB1710738.4A GB201710738D0 (en) | 2017-06-22 | 2017-07-04 | Anti-arrhythmic drug intermediate 1-(2,6 dimethroxy)-2-acetone synthesis method |
| IES20180108 IES20180108A2 (en) | 2017-06-22 | 2018-04-04 | Anti-arrhythmic drug intermediate 1-(2,6 dimethroxy)-2-acetone synthesis method |
| AU2018100532A AU2018100532A4 (en) | 2017-06-22 | 2018-04-24 | Anti-arrhythmic drug intermediate 1-(2,6-dimethoxy)-2-acetone synthesis method |
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|---|---|---|---|
| CN201710482856.0A CN108238864A (en) | 2017-06-22 | 2017-06-22 | The synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxys) -2- acetone |
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| Publication Number | Publication Date |
|---|---|
| CN108238864A true CN108238864A (en) | 2018-07-03 |
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| CN201710482856.0A Pending CN108238864A (en) | 2017-06-22 | 2017-06-22 | The synthetic method of antiarrhythmic drug intermediate 1- (2,6- dimethoxys) -2- acetone |
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|---|---|
| CN (1) | CN108238864A (en) |
| AU (1) | AU2018100532A4 (en) |
| GB (1) | GB201710738D0 (en) |
| IE (1) | IES20180108A2 (en) |
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2017
- 2017-06-22 CN CN201710482856.0A patent/CN108238864A/en active Pending
- 2017-07-04 GB GBGB1710738.4A patent/GB201710738D0/en not_active Ceased
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2018
- 2018-04-04 IE IES20180108 patent/IES20180108A2/en not_active Application Discontinuation
- 2018-04-24 AU AU2018100532A patent/AU2018100532A4/en not_active Ceased
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| Publication number | Publication date |
|---|---|
| AU2018100532A4 (en) | 2018-05-24 |
| GB201710738D0 (en) | 2017-08-16 |
| IES20180108A2 (en) | 2019-11-13 |
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