CN108238886A - The synthetic method of chlormadinone pharmaceutical intermediate neighbour's tetrachloroquinone - Google Patents
The synthetic method of chlormadinone pharmaceutical intermediate neighbour's tetrachloroquinone Download PDFInfo
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- CN108238886A CN108238886A CN201710706464.8A CN201710706464A CN108238886A CN 108238886 A CN108238886 A CN 108238886A CN 201710706464 A CN201710706464 A CN 201710706464A CN 108238886 A CN108238886 A CN 108238886A
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- C—CHEMISTRY; METALLURGY
- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses the synthetic methods of chlormadinone pharmaceutical intermediate neighbour's tetrachloroquinone, include the following steps：2,3 dihydroxy, 4,5,6 trichloroaniline is added in reaction vessel, cyclohexane solution slowly increases temperature, increases temperature, then adds in potassium sulfate solution, reacts；2,3 dichloropropylene solution are continuously added, reduce temperature, three carbonyl cyclopentadienyl manganeses are added in batches, control mixing speed, the reaction was continued, solution is layered, and is reduced temperature, is washed repeatedly with sodium chloride solution, ethylene oxide solution washing is multiple, the washing of Isosorbide-5-Nitrae dichloroetane solution is multiple, is recrystallized in dichloropentane solution, dehydrating agent is dehydrated, and obtains finished product neighbour's tetrachloroquinone.
Description
Technical field
The present invention relates to a kind of preparation methods of medicine intermediate, belong to organic synthesis field more particularly to chlormadinone
The synthetic method of pharmaceutical intermediate neighbour's tetrachloroquinone.
Background technology
Adjacent tetrachloroquinone is mainly as chlormadinone drug synthesis intermediate and organic synthesis dehydrating agent.Existing synthesis
Method is obtained mostly using pentachlorophenol in chloroform with nitric acid reaction.But this synthetic method is needed using nitric acid as reaction
One of object, more demanding to equipment corrosion resistance since nitric acid corrosive power and oxidability are stronger, device fabrication and maintenance
Cost is higher, is unfavorable for reducing production cost, and entire building-up process 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 the conjunction of ground progesterone pharmaceutical intermediate neighbour's tetrachloroquinone
Into method, include the following steps：
A:2,3- dihydroxy -4,5, tri- chloro- aniline of 6- are added in reaction vessel, cyclohexane solution slowly increases temperature,
Temperature is increased in 90-130min to 25-31 DEG C, potassium sulfate solution is then added in, reacts 1-2h；
B:2,3- dichloropropylene solution is continuously added, temperature is reduced to 15-22 DEG C, adds in three carbonyl cyclopentadienyl manganeses in batches,
Mixing speed 150-180rpm, the reaction was continued 90-130min are controlled, solution layering reduces temperature to 5-9 DEG C, molten with sodium chloride
Liquid washing is multiple, and ethylene oxide solution washing is multiple, and Isosorbide-5-Nitrae-dichloroetane solution washing is multiple, is tied again in dichloropentane solution
Crystalline substance, dehydrating agent dehydration, obtains finished product neighbour's tetrachloroquinone.
Preferably, cyclohexane solution mass fraction is 20-26%.
Preferably, potassium sulfate solution mass fraction is 10-15%.
Preferably, 2,3- dichloropropylenes liquid quality fraction is 35-42%.
Preferably, sodium chloride solution mass fraction is 10-16%.
Preferably, ethylene oxide solution mass fraction is 40-46%.
Preferably, Isosorbide-5-Nitrae-dichloroetane liquid quality fraction is 50-55%.
Preferably, dichloropentane liquid quality fraction is 75-83%.
Entire building-up process can be used following net reaction to represent：
Compared to synthetic method disclosed in background technology, ground provided by the invention progesterone pharmaceutical intermediate neighbour's tetrachloroquinone
Synthetic method, this synthetic method do not need to avoid as reactant using nitric acid nitric acid corrosive power and oxidability compared with
The adverse effect more demanding to equipment corrosion resistance by force, reduces device fabrication and maintenance cost, so as to advantageously reduce
Production cost, reaction intermediate link reduce very much, and the reaction time also shortens much, and reaction yield also improves, while this hair
It is bright to provide a kind of new synthetic route, it lays a good foundation further to promote reaction yield.
Description of the drawings
Fig. 1 is the infrared analysis spectrogram of finished product neighbour's tetrachloroquinone.
Specific embodiment
Embodiment 1：
The synthetic method of ground progesterone pharmaceutical intermediate neighbour's tetrachloroquinone, includes the following steps：
A:3mol 2 is added in reaction vessel, 3- dihydroxy -4,5, tri- chloro- aniline of 6-, 1.3L mass fractions are 20%
Cyclohexane solution, slowly increase temperature, temperature increased in 90min to 25 DEG C, it is 10% then to add in 800ml mass fractions
Potassium sulfate solution, react 1h；
B:2, the 3- dichloropropylene solution that 6mol mass fractions are 35% is continuously added, reduces temperature to 15 DEG C, in batches
Tri- carbonyl cyclopentadienyl manganeses of 3mol are added in, control mixing speed 150rpm, the reaction was continued 90min, solution layering reduces temperature to 5 DEG C,
It is washed 3 times with the sodium chloride solution that mass fraction is 10%, the ethylene oxide solution that mass fraction is 40% is washed 5 times, quality
Isosorbide-5-Nitrae-dichloroetane solution that score is 50% washs 2 times, is recrystallized in the dichloropentane solution for being 75% in mass fraction, nothing
Water magnesium sulfate dehydrating agent is dehydrated, and obtains finished product neighbour tetrachloroquinone 641.77g, yield 87%.
Embodiment 2：
The synthetic method of ground progesterone pharmaceutical intermediate neighbour's tetrachloroquinone, includes the following steps：
A:Addition 3mol 2,3- dihydroxy -4,5, tri- chloro- aniline of 6-, 1.3L mass fractions are in reaction vessel
23.5% cyclohexane solution, slowly increases temperature, and temperature is increased in 110min to 28 DEG C, then adds in 800ml mass point
Number is 12.5% potassium sulfate solution, reacts 1.5h；
B:2, the 3- dichloropropylene solution that 6.5mol mass fractions are 37% is continuously added, reduces temperature to 17 DEG C, in batches
Secondary addition tri- carbonyl cyclopentadienyl manganeses of 3.5mol, control mixing speed 165rpm, the reaction was continued 110min, solution layering, reduction temperature
It to 7 DEG C, is washed 4 times with the sodium chloride solution that mass fraction is 13%, the ethylene oxide solution washing 6 that mass fraction is 43%
Secondary, Isosorbide-5-Nitrae-dichloroetane solution that mass fraction is 52.5% washs 3 times, in the dichloropentane solution for being 79% in mass fraction
Recrystallization, anhydrous calcium chloride dehydrating agent dehydration, obtains finished product neighbour tetrachloroquinone 671.28g, yield 91%.
Embodiment 3：
The synthetic method of ground progesterone pharmaceutical intermediate neighbour's tetrachloroquinone, includes the following steps：
A:3mol 2 is added in reaction vessel, 3- dihydroxy -4,5, tri- chloro- aniline of 6-, 1.3L mass fractions are 26%
Cyclohexane solution, slowly increase temperature, in 130min increase temperature to 31 DEG C, then add in 800ml mass fractions be
15% potassium sulfate solution reacts 2h；
B:2, the 3- dichloropropylene solution that 7mol mass fractions are 42% is continuously added, reduces temperature to 22 DEG C, in batches
Tri- carbonyl cyclopentadienyl manganeses of 4mol are added in, control mixing speed 180rpm, the reaction was continued 130min, solution layering, reduction temperature to 9
DEG C, it is washed 5 times with the sodium chloride solution that mass fraction is 16%, the ethylene oxide solution that mass fraction is 46% is washed 7 times, matter
It measures Isosorbide-5-Nitrae-dichloroetane solution that score is 55% to wash 4 times, be recrystallized in the dichloropentane solution for being 83% in mass fraction,
Anhydrous magnesium sulfate dehydrating agent is dehydrated, and obtains finished product neighbour tetrachloroquinone 693.41g, yield 94%.
Infrared analysis is made to finished product neighbour's tetrachloroquinone, obtains infrared analysis spectrogram, as shown in Figure 1.
Infrared analysis data are as shown in table 1.
1 infrared analysis data of table
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 (9)
1. the synthetic method of ground progesterone pharmaceutical intermediate neighbour's tetrachloroquinone, which is characterized in that include the following steps：
A:2,3- dihydroxy -4,5, tri- chloro- aniline of 6- are added in reaction vessel, cyclohexane solution slowly increases temperature,
In 90-130min then raising temperature adds in potassium sulfate solution to 25-31 DEG C, reacts 1-2h；
B:2,3- dichloropropylene solution is continuously added, temperature is reduced to 15-22 DEG C, adds in three carbonyl cyclopentadienyl manganeses in batches, control
Mixing speed 150-180rpm, the reaction was continued 90-130min, solution layering reduce temperature to 5-9 DEG C, are washed with sodium chloride solution
It washs repeatedly, ethylene oxide solution washing is multiple, and Isosorbide-5-Nitrae-dichloroetane solution washing is multiple, is recrystallized in dichloropentane solution,
Dehydrating agent is dehydrated, and obtains finished product neighbour's tetrachloroquinone.
2. the synthetic method of progesterone pharmaceutical intermediate neighbour tetrachloroquinone according to claim 1, which is characterized in that described
Cyclohexane solution mass fraction is 20-26%.
3. the synthetic method of progesterone pharmaceutical intermediate neighbour tetrachloroquinone according to claim 1, which is characterized in that described
Potassium sulfate solution mass fraction is 10-15%.
4. the synthetic method of progesterone pharmaceutical intermediate neighbour tetrachloroquinone according to claim 1, which is characterized in that described
2,3- dichloropropylenes liquid quality fraction is 35-42%.
5. the synthetic method of progesterone pharmaceutical intermediate neighbour tetrachloroquinone according to claim 1, which is characterized in that described
Sodium chloride solution mass fraction is 10-16%.
6. the synthetic method of progesterone pharmaceutical intermediate neighbour tetrachloroquinone according to claim 1, which is characterized in that described
Ethylene oxide solution mass fraction is 40-46%.
7. the synthetic method of progesterone pharmaceutical intermediate neighbour tetrachloroquinone according to claim 1, which is characterized in that described
1,4- dichloroetane liquid quality fraction is 50-55%.
8. the synthetic method of progesterone pharmaceutical intermediate neighbour tetrachloroquinone according to claim 1, which is characterized in that described
Dichloropentane liquid quality fraction is 75-83%.
9. the synthetic method of progesterone pharmaceutical intermediate neighbour tetrachloroquinone according to claim 1, which is characterized in that including such as
Lower step：
A:3mol 2 is added in reaction vessel, 3- dihydroxy -4,5, tri- chloro- aniline of 6-, 1.3L mass fractions are 26% ring
Hexane solution slowly increases temperature, and temperature is increased in 130min to 31 DEG C, and it is 15% then to add in 800ml mass fractions
Potassium sulfate solution reacts 2h；
B:2, the 3- dichloropropylene solution that 7mol mass fractions are 42% is continuously added, temperature is reduced to 22 DEG C, adds in batches
Tri- carbonyl cyclopentadienyl manganeses of 4mol, control mixing speed 180rpm, the reaction was continued 130min, and solution layering reduces temperature to 9 DEG C, uses
The sodium chloride solution that mass fraction is 16% washs 5 times, and the ethylene oxide solution that mass fraction is 46% is washed 7 times, quality point
Number washs 4 times for 55% Isosorbide-5-Nitrae-dichloroetane solution, is recrystallized in the dichloropentane solution for being 83% in mass fraction, is dehydrated
Agent is dehydrated, and obtains finished product neighbour's tetrachloroquinone.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710706464.8A CN108238886A (en) | 2017-08-19 | 2017-08-19 | The synthetic method of chlormadinone pharmaceutical intermediate neighbour's tetrachloroquinone |
| GBGB1713868.6A GB201713868D0 (en) | 2017-08-19 | 2017-08-30 | Chlormadinone drug intermediates o-tetrachlorobenzoquinone synthesis method |
| AU2018100844A AU2018100844A4 (en) | 2017-08-19 | 2018-06-20 | Chlormadinone drug intermediates o-tetrachlorobenzoquinone synthesis method |
| IES20180203 IES20180203A2 (en) | 2017-08-19 | 2018-06-26 | Chlormadinone drug intermediates o-tetrachlorobenzoquinone synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710706464.8A CN108238886A (en) | 2017-08-19 | 2017-08-19 | The synthetic method of chlormadinone pharmaceutical intermediate neighbour's tetrachloroquinone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108238886A true CN108238886A (en) | 2018-07-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710706464.8A Pending CN108238886A (en) | 2017-08-19 | 2017-08-19 | The synthetic method of chlormadinone pharmaceutical intermediate neighbour's tetrachloroquinone |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN108238886A (en) |
| AU (1) | AU2018100844A4 (en) |
| GB (1) | GB201713868D0 (en) |
| IE (1) | IES20180203A2 (en) |
-
2017
- 2017-08-19 CN CN201710706464.8A patent/CN108238886A/en active Pending
- 2017-08-30 GB GBGB1713868.6A patent/GB201713868D0/en not_active Ceased
-
2018
- 2018-06-20 AU AU2018100844A patent/AU2018100844A4/en not_active Ceased
- 2018-06-26 IE IES20180203 patent/IES20180203A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU2018100844A4 (en) | 2018-08-09 |
| IES20180203A2 (en) | 2019-11-13 |
| GB201713868D0 (en) | 2017-10-11 |
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Application publication date: 20180703 |