CN102977072B - Synthesis method of 2,8-dimethyl phenoxathiin - Google Patents
Synthesis method of 2,8-dimethyl phenoxathiin Download PDFInfo
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- CN102977072B CN102977072B CN201110259329.6A CN201110259329A CN102977072B CN 102977072 B CN102977072 B CN 102977072B CN 201110259329 A CN201110259329 A CN 201110259329A CN 102977072 B CN102977072 B CN 102977072B
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- evil thiophene
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Abstract
The invention discloses a synthesis method of 2,8-dimethyl phenoxathiin. The synthesis method comprises the following steps of adding 4,4-dimethyl diphenyl ether into a reaction pot, adding anhydrous aluminum trichloride into the reaction pot at a temperature within 40 DEG C, adding sulfur powder into the reaction pot in batches with stirring, carrying out a condensation reaction process, carrying out aftertreatment, and carrying out vacuum fractionation of a crude product to obtain a crude product of 2,8-dimethyl phenoxathiin, adding the crude product of 2,8-dimethyl phenoxathiin into methanol for recrystallization, cooling to a temperature of 0 DEG C, carrying out heat preservation for 5-6h, and carrying out centrifugation, decompression, and drying to obtain a finished product of 2,8-dimethyl phenoxathiin. The synthesis method reduces a condensation reaction temperature, shortens reaction time, controls the incidence of a side reaction, improves a product yield, reduces a production cost, reduces a discharge amount of three wastes in the whole process, and satisfies production requirements of environmental protection and cleanness.
Description
Technical field
The present invention relates to medicine and chemical technology field, particularly relate to synthetic method that is a kind of 2,8-dimethyl Fen Evil thiophene.
Background technology
2,8-dimethyl Fen Evil thiophene, structure formula is by shown in following formula (I), and outward appearance is micro-yellow powder solid, it is the important medicine intermediate of a class epithio shape analog derivative, can be present in the pharmaceutical molecules structure of different pharmacological action, be mainly used in synthesizing vessel softening, promote metabolism class medicine.In prior art, 2, the synthesis technique production cost of 8-methyl phenoxazine thiophene is high, purity is low, and three waste discharge is large, and technical difficulty is large, and condition is harsh, and its purposes of extreme influence and consumption are promoted.
Summary of the invention
The technical problem that the present invention mainly solves be to provide a kind of cost, purity high, pollute that little, technique is simple 2, the synthetic method of 8-dimethyl Fen Evil thiophene.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is: provide a kind of 2, the synthetic method of 8-dimethyl Fen Evil thiophene, and described synthetic method comprises following preparation process:
(1) condensation reaction: by 4, 4-dimethyl phenyl ether joins in reactor, aluminum trichloride (anhydrous) is dropped in 40 DEG C, add SULPHUR POWDER under stirring in batches, control temperature is at 55-60 DEG C, be incubated after 1-1.5 hour, be warming up to 105-110 DEG C, insulation reaction 2-3h, be cooled to less than 40 DEG C, obtain reaction solution, then in reaction solution, add anhydrous methylene chloride and ice sour water, control temperature is below 40 DEG C, finish stirring 1 hour, stratification, the oil reservoir sodium carbonate solution of 20% is neutralized to PH=6-7, continue stratification, organic layer is washed again with clear water, separate organic layer and proceed to precipitation pot, purify ethylene dichloride, obtain crude reaction, crude product vacuum fractionation, first steam unreacted raw material 4, 4-dimethyl phenyl ether, steam 2 again, 8-dimethyl Fen Evil thiophene crude product, by product discards, the raw materials recovery recycled steamed,
(2) refining: by 2 of distillation gained, 8-dimethyl Fen Evil thiophene crude product joins recrystallization in methyl alcohol, be cooled to 0 DEG C keep 5-6h after, centrifugal, reduce pressure, dry to obtain 2,8-dimethyl Fen Evil thiophene finished products.
In a preferred embodiment of the present invention, in described condensation reaction, 4,4-dimethyl phenyl ether, aluminum trichloride (anhydrous) and SULPHUR POWDER mass ratio be 9-10: 4-5: 1.
In a preferred embodiment of the present invention, described ice sour water is concentrated hydrochloric acid and water is 1: 3 mixture formed according to mass ratio.
In a preferred embodiment of the present invention, in described condensation reaction, the mass ratio of reaction solution, anhydrous methylene chloride and ice sour water is 1: 3-4: 1.
In a preferred embodiment of the present invention, described weak caustic solution is the one in sodium carbonate solution, solution of potassium carbonate, sodium hydroxide solution or ammoniacal liquor.
In a preferred embodiment of the present invention, in described condensation reaction, first steam unreacted raw material 4,4-dimethyl phenyl ether technological process for controlling under vacuum tightness is 5mmHg, collect the cut of 140 DEG C-150 DEG C.
In a preferred embodiment of the present invention, in described condensation reaction, then the technological process steaming 2,8-dimethyl Fen Evil thiophene finished product is for controlling under vacuum tightness is 5mmHg, collects the cut of 180 DEG C-185 DEG C.
In a preferred embodiment of the present invention, described 2,8-dimethyl Fen Evil thiophene finished product joins recrystallization in methyl alcohol, and 2, the ratio of 8-dimethyl Fen Evil thiophene finished product and methyl alcohol is: 2,8-dimethyl Fen Evil thiophene finished product (kg): methyl alcohol (L)=1: 4-5.
Compared with prior art, beneficial effect of the present invention is:
1, the present invention reduces setting-up point, Reaction time shorten, controls the generation of side reaction, improves product yield, reduces production cost.
2, aftertreatment of the present invention is by adding low boiling point solvent, alleviates post-processing difficulty, decreases the quantity discharged of the whole process three wastes, meets the production requirement of environment-protecting clean.
3, this synthesis technique has obvious economic benefit and environmental benefit, is conducive to realizing suitability for industrialized production.
Embodiment
The invention discloses synthetic method that is a kind of 2,8-dimethyl Fen Evil thiophene, described synthetic method comprises following preparation process:
(1) condensation reaction: by 4, 4-dimethyl phenyl ether joins in reactor, aluminum trichloride (anhydrous) is dropped in 40 DEG C, add SULPHUR POWDER under stirring in batches, control temperature is at 55-60 DEG C, be incubated after 1-1.5 hour, be warming up to 105-110 DEG C, insulation reaction 2-3h, be cooled to less than 40 DEG C, obtain reaction solution, then in reaction solution, add anhydrous methylene chloride and ice sour water, control temperature is below 40 DEG C, finish stirring 1 hour, stratification, organic layer alkaline solution is neutralized to PH=6-7, continue stratification, organic layer is washed again with clear water, separate organic layer and proceed to precipitation pot, purify ethylene dichloride, obtain crude reaction, crude product vacuum fractionation, first steam unreacted raw material 4, 4-dimethyl phenyl ether, steam 2 again, 8-dimethyl Fen Evil thiophene crude product, by product discards, the raw materials recovery recycled steamed.
(2) refining: by 2 of distillation gained, 8-dimethyl Fen Evil thiophene crude product joins recrystallization in methyl alcohol, be cooled to 0 DEG C keep 5-6h after, centrifugal, reduce pressure, dry to obtain 2,8-dimethyl Fen Evil thiophene finished products.
Wherein, in condensation reaction of the present invention, 4,4-dimethyl phenyl ether, aluminum trichloride (anhydrous) and SULPHUR POWDER mass ratio be 9-10: 4-5: 1; Described ice sour water is concentrated hydrochloric acid and water is 1: 3 mixture formed according to mass ratio; In described condensation reaction, the mass ratio of reaction solution, anhydrous methylene chloride and ice sour water is 1: 3-4: 1; Described weak caustic solution is the one in sodium carbonate solution, solution of potassium carbonate, sodium hydroxide solution or ammoniacal liquor; In described condensation reaction, first steam unreacted raw material 4,4-dimethyl phenyl ether technological process for controlling under vacuum tightness is 5mmHg, collect the cut of 140 DEG C-150 DEG C; In described condensation reaction, then the technological process steaming 2,8-dimethyl Fen Evil thiophene finished product is for controlling under vacuum tightness is 5mmHg, collects the cut of 180 DEG C-185 DEG C; 2,8-described dimethyl Fen Evil thiophene finished products join recrystallization in methyl alcohol, and 2, the ratio of 8-dimethyl Fen Evil thiophene finished product and methyl alcohol is: 2,8-dimethyl Fen Evil thiophene finished product (kg): methyl alcohol (L)=1: 4-5.
Embodiment 1
Condensation reaction: by 450kg 4, 4-dimethyl phenyl ether joins in reactor, 200kg aluminum trichloride (anhydrous) is dropped in 40 DEG C, add 50kg SULPHUR POWDER under stirring in batches, control temperature is at 55-60 DEG C, be incubated after 1-1.5 hour, be warming up to 105-110 DEG C, insulation reaction 2-3h, be cooled to less than 40 DEG C, obtain reaction solution, then in reaction solution, 1000kg anhydrous methylene chloride and 1000kg ice sour water is added (wherein, hydrochloric acid 250kg, water 750kg), control temperature is below 40 DEG C, finish stirring 1 hour, stratification, the sodium carbonate solution of organic layer 200L20% is neutralized to PH=6-7, continue stratification, again with 1000L clear water washing organic layer, separate organic layer and proceed to precipitation pot, purify ethylene dichloride, obtain crude reaction, crude product vacuum fractionation, under vacuum tightness is 5mmHg, collect the cut of 140 DEG C-150 DEG C.First steam unreacted raw material 4,4-dimethyl phenyl ether, continue under vacuum tightness is 5mmHg, collect the cut of 180 DEG C-185 DEG C, then steam 2,8-dimethyl Fen Evil thiophene crude product 426.06kg, by product discards, the raw materials recovery recycled steamed.
Refining: by 2 of distillation gained, 8-dimethyl Fen Evil thiophene crude product 426.06kg joins recrystallization in 1704.2L methyl alcohol, after being cooled to 0 DEG C of maintenance 5-6h, centrifugal, decompression, dry 2,8-dimethyl Fen Evil thiophene finished product 383.45kg, productive rate 74% (in 4,4-dimethyl phenyl ether), content 99.40%, fugitive constituent < 0.1%, fusing point 68-69 DEG C.
Embodiment 2
Condensation reaction: by 950kg 4, 4-dimethyl phenyl ether joins in reactor, 450kg aluminum trichloride (anhydrous) is dropped in 40 DEG C, add 100kg SULPHUR POWDER under stirring in batches, control temperature is at 55-60 DEG C, be incubated after 1-1.5 hour, be warming up to 105-110 DEG C, insulation reaction 2-3h, be cooled to less than 40 DEG C, obtain reaction solution, then in reaction solution, 2000kg anhydrous methylene chloride and 2000kg ice sour water is added (wherein, hydrochloric acid 500kg, water 1500kg), control temperature is below 40 DEG C, finish stirring 1 hour, stratification, the salt of wormwood H=6-7 of organic 400L 20%, continue stratification, again with 2000L clear water washing organic layer, separate organic layer and proceed to precipitation pot, purify ethylene dichloride, obtain crude reaction, crude product vacuum fractionation, under vacuum tightness is 5mmHg, collect the cut of 140 DEG C-150 DEG C.First steam unreacted raw material 4,4-dimethyl phenyl ether, continue under vacuum tightness is 5mmHg, collect the cut of 180 DEG C-185 DEG C, then steam 2,8-dimethyl Fen Evil thiophene crude product 934.15kg, by product discards, the raw materials recovery recycled steamed.
Refining: the 934.15kg 2 of distillation gained, 8-dimethyl Fen Evil thiophene crude product are joined recrystallization in 3736.58L methyl alcohol, after being cooled to 0 DEG C of maintenance 5-6h, centrifugal, decompression, dry 2,8-dimethyl Fen Evil thiophene finished product 831.39kg, productive rate 76% (in 4,4-dimethyl phenyl ether), content 99.88%, fugitive constituent < 0.1%, fusing point 69-70 DEG C.
Embodiment 3
Condensation reaction: by 1500kg 4, 4-dimethyl phenyl ether joins in reactor, 750kg aluminum trichloride (anhydrous) is dropped in 40 DEG C, add 150kg SULPHUR POWDER under stirring in batches, add SULPHUR POWDER under stirring in batches, control temperature is at 55-60 DEG C, be incubated after 1-1.5 hour, be warming up to 105-110 DEG C, insulation reaction 2-3h, be cooled to less than 40 DEG C, obtain reaction solution, then in reaction solution, add anhydrous methylene chloride and ice sour water, control temperature is below 40 DEG C, finish stirring 1 hour, stratification, the oil reservoir sodium carbonate solution of 20% is neutralized to PH=6-7, continue stratification, organic layer is washed again with clear water, separate organic layer and proceed to precipitation pot, purify ethylene dichloride, obtain crude reaction, crude product vacuum fractionation, first steam unreacted raw material 4, 4-dimethyl phenyl ether, steam 2 again, 8-dimethyl Fen Evil thiophene crude product 1423.57kg, by product discards, the raw materials recovery recycled steamed.
Refining: by 2 of distillation gained, 8-dimethyl Fen Evil thiophene crude product 1423.57kg joins recrystallization in methyl alcohol, after being cooled to 0 DEG C of maintenance 5-6h, centrifugal, decompression, dry 2,8-dimethyl Fen Evil thiophene finished product 1295.45kg, productive rate 75% (in 4,4-dimethyl phenyl ether), content 99.4%, fugitive constituent < 0.1%, fusing point 68-69 DEG C.
The present invention reduces setting-up point, regulates reaction rhythm, controls the generation of side reaction, improve product yield, reduce production cost; Aftertreatment of the present invention, by adding low boiling point solvent, alleviates post-processing difficulty, decreases the quantity discharged of the whole process three wastes, meets the production requirement of environment-protecting clean; This synthesis technique has obvious economic benefit and environmental benefit, is conducive to realizing suitability for industrialized production.
The foregoing is only embodiments of the invention; not thereby the scope of the claims of the present invention is limited; every utilize description of the present invention to do equivalent structure or equivalent flow process conversion; or be directly or indirectly used in other relevant technical fields, be all in like manner included in scope of patent protection of the present invention.
Claims (1)
1. 2, the synthetic method of 8-dimethyl fen Evil thiophene, it is characterized in that, described synthetic method comprises following preparation process:
(1) condensation reaction: by 4, 4-dimethyl phenyl ether joins in reactor, aluminum trichloride (anhydrous) is dropped in 40 DEG C, add SULPHUR POWDER under stirring in batches, control temperature is at 55-60 DEG C, be incubated after 1-1.5 hour, be warming up to 105-110 DEG C, insulation reaction 2-3h, be cooled to less than 40 DEG C, obtain reaction solution, then in reaction solution, add anhydrous methylene chloride and ice sour water, control temperature is below 40 DEG C, finish, stir 1 hour, stratification, organic layer alkaline solution is neutralized to PH=6-7, continue stratification, organic layer is washed again with clear water, separate organic layer and proceed to precipitation pot, purify ethylene dichloride, obtain crude reaction, crude product vacuum fractionation, under vacuum tightness is 5mmHg, first steam unreacted raw material 4, 4-dimethyl phenyl ether, collect the cut of 140 DEG C-150 DEG C, steam 2 again, 8-dimethyl Fen Evil thiophene crude product, by product discards, the raw materials recovery recycled steamed, wherein, 4, 4-dimethyl phenyl ether, the mass ratio of aluminum trichloride (anhydrous) and SULPHUR POWDER is 9-10:4-5:1,
(2) refining: by 2 of distillation gained, 8-dimethyl Fen Evil thiophene crude product joins recrystallization in methyl alcohol, be cooled to 0 DEG C keep 5-6h after, centrifugal, reduce pressure, dry 2,8-dimethyl Fen Evil thiophene finished product.
2. the synthetic method of according to claim 12,8-dimethyl Fen Evil thiophene, it is characterized in that, described ice sour water is concentrated hydrochloric acid and water is the mixture that 1:3 is formed according to mass ratio.
3. the synthetic method of according to claim 12,8-dimethyl Fen Evil thiophene, it is characterized in that, in described condensation reaction, the mass ratio of reaction solution, anhydrous methylene chloride and ice sour water is 1:3-4:1.
4. the synthetic method of according to claim 12,8-dimethyl Fen Evil thiophene, it is characterized in that, described weak caustic solution is the one in sodium carbonate solution, solution of potassium carbonate, sodium hydroxide solution or ammoniacal liquor.
5. according to the synthetic method of 2 described in claim 1,8-dimethyl Fen Evil thiophene, it is characterized in that, in described condensation reaction, then steam 2, the technological process of 8-dimethyl Fen Evil thiophene finished product for controlling under vacuum tightness is 5mmHg, collect the cut of 180 DEG C-185 DEG C.
6. the synthetic method of according to claim 12,8-dimethyl Fen Evil thiophene, it is characterized in that, described 2,8-dimethyl Fen Evil thiophene finished product joins recrystallization in methyl alcohol, and 2, the ratio of 8-dimethyl Fen Evil thiophene finished product and methyl alcohol is: 2,8-dimethyl Fen Evil thiophene finished product (kg): methyl alcohol (L)=1:4-5.
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| CN201110259329.6A CN102977072B (en) | 2011-09-05 | 2011-09-05 | Synthesis method of 2,8-dimethyl phenoxathiin |
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| CN201110259329.6A CN102977072B (en) | 2011-09-05 | 2011-09-05 | Synthesis method of 2,8-dimethyl phenoxathiin |
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| CN102977072B true CN102977072B (en) | 2015-05-27 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4647709A (en) * | 1984-08-31 | 1987-03-03 | Hoechst Aktiengesellschaft | Process for ring-chlorinating toluene |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4647709A (en) * | 1984-08-31 | 1987-03-03 | Hoechst Aktiengesellschaft | Process for ring-chlorinating toluene |
Non-Patent Citations (1)
| Title |
|---|
| Steps towards a practical synthesis of macrocyclic bisbenzylisoquinolines;Y.M.Al-Hiari et al;《Journal of Heterocyclic Chemistry》;20050630;第42卷(第4期);647-659 * |
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