CN1958578A - Method for preparing dichloroquinoxaline, and nitro-derivative - Google Patents
Method for preparing dichloroquinoxaline, and nitro-derivative Download PDFInfo
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- CN1958578A CN1958578A CNA2006100545827A CN200610054582A CN1958578A CN 1958578 A CN1958578 A CN 1958578A CN A2006100545827 A CNA2006100545827 A CN A2006100545827A CN 200610054582 A CN200610054582 A CN 200610054582A CN 1958578 A CN1958578 A CN 1958578A
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Abstract
This invention relates to a novel method for preparing the compound shown in formula I. R1 and R2 can both be H or nitryl, or one is H and the other is nitryl. The method comprises: heat-refluxing the compound shown in formula II and diethyl oxalate in HCl to obtain the compound shown in formula III, nitrifying to obtain the compound shown in formula IV, chlorinating, extracting with an organic solvent, and recrystallizing to obtain the compound shown in formula I. Experiments show that the method has such advantages as high yield, low cost and easy operation, and is suitable for mass production.
Description
Technical field
The new preparation process of the formula I compound that the present invention relates to.
The feature of formula I compound is: R
1, R
2Can be hydrogen atom; Perhaps be nitro, perhaps one is hydrogen atom, and another is a nitro.Some derivatives of formula I compound are noncompetitive nmda receptor antagonists, can be used as neuroprotective drug, anticonvulsive drug and anodyne, and may be to the effective (J.Med.Chem of nervous system degenerative diseases such as Parkinson's disease, senile dementia, alzheimer's disease, 1994, (37): 467-475); Simultaneously it also be synthesizing quinoxaline kind anti-cancer drugs thing, antifungal drug, central nervous system tranquilizer and radio-protector etc. intermediate (Indian Journal of Chemistry, 1988, (27B): 1110-1112); Also can be used for preparing (Chem.Lett, 1996, (5): 369-370) such as fluorescence derivating agent, multiple polyester fiber dyestuff.
Background technology
Existing about 2, in the synthetic route of 3-dichloro-quinoxaline and nitro-derivative thereof, mainly comprise following bibliographical information:
Route 1: formula I compound characteristic is: R
1, R
2When being hydrogen atom, the preparation method is: to contain 2%N, 1 of dinethylformamide, 4-dioxane be as solvent, with thionyl chloride as chlorizating agent, carry out formula IV compound chloro, the gained crude product is used the chloroform recrystallization, gets formula I compound (J Heterocyclic Chem, 1992,29 (4): 771-777.).In this route 1,4-dioxane solvent-oil ratio is big, cost is high, and chloroform is big to human body harm.
Route 2: formula I compound characteristic is: R
1, R
2When being nitro, the preparation method is: the nitrated formula III compound of the saltpetre and the vitriol oil or trifluoroacetic acid gets formula IV compound, at phosphorus oxychloride and N, chlorination formula IV compound in the mixed solution of accelerine, behind a large amount of benzene extraction reactants, the dehydrated alcohol recrystallization gets formula I compound.Harmful and benzene contaminate environment of this route, yield lower (J.Chem.Soc, 1962,1170-1176).
Route 3: formula I compound characteristic is: R
1, R
2One is hydrogen atom, and when another was nitro, the preparation method was: at first the formula III compound is synthesized in 4-nitro O-Phenylene Diamine and oxalic acid cyclisation, divides two synthetic routes to carry out chloro again, makes formula I compound.Synthetic route 1: containing 2%N, 1 of N-methylformamide, the 4-dioxane is as solvent, carry out chloro with thionyl chloride as chlorizating agent, the gained crude product is used the chloroform recrystallization, get formula I compound (J Heterocyclic Chem, 1992,29 (4): 771-777); Synthetic route 2: make chlorizating agent with phosphorus oxychloride, need under nitrogen protection back flow reaction; after the cooling, pour reaction solution into frozen water again, use dichloromethane extraction; collected organic layer is removed methylene dichloride after the drying, the gained solid; with the isopropyl ether washing, promptly get formula I compound (WO9732858), the weak point of these synthetic routes is: raw material is difficult to obtain; and the cost height, long reaction time, product colour is darker; post-processing difficulty is increased, be unfavorable for suitability for industrialized production.
The content of invention
At prior art synthetic route above shortcomings, the purpose of this invention is to provide a kind of economical, environment-friendly type, and have 2 of industrialization prospect, the new preparation process of 3-dichloro-quinoxaline and nitro-derivative thereof.
For realizing that the present invention simplifies synthesis technique, reduces cost, improves yield, be easy to the purpose of industrialization and the technical scheme that adopts is such: promptly, the synthetic route of formula I compound is improved and optimized; In hydrochloric acid soln,, make the formula III compound with O-Phenylene Diamine and oxalic acid diethyl ester cyclization; It is nitrated to make nitrating agent with saltpetre and the vitriol oil or trifluoroacetic acid, makes formula IV compound; Adopt phosphorus oxychloride and N, dinethylformamide mixed solvent chloro can make formula I compound.
According to technique scheme, the new preparation process of the formula I compound that the present invention relates to is as follows:
In the formula I compound: R
1, R
2Can be hydrogen atom; Perhaps be nitro, perhaps one is hydrogen atom, and another is a nitro;
This method comprises the steps:
1), ring-closure reaction: in hydrochloric acid soln, O-Phenylene Diamine and oxalic acid diethyl ester under 70～80 ℃, reacted 90～120 minutes, made the formula III compound.Reaction formula is as follows:
2), nitration reaction: the formula III compound and the vitriol oil are cooled to 0 ℃, add nitrating agent, kept 20～40 minutes, at room temperature react 3～5 hours again after, reaction solution is poured in the frozen water, separate out solid, be formula IV compound, reaction formula is as follows:
In the formula IV compound: R
1, R
2Be nitro, perhaps one is to be hydrogen atom, and another is a nitro.
3), chlorination reaction: formula IV compound is added phosphorus oxychloride, or phosphorus oxychloride and N, the dinethylformamide mixed solvent refluxes down at 100～110 ℃, in formula IV compound: R
1, R
2During for nitro, the reaction times is 120～135 minutes; Or in formula IV compound: R
1, R
2One is to be hydrogen atom, and when another was nitro, the reaction times was 90～120 minutes, and in reaction solution impouring frozen water, the gained solid promptly makes the formula I compound of white solid with organic solvent extraction and recrystallization, and yield is not less than 80%, and reaction formula is as follows:
Or 4), chlorination reaction: the formula III compound is added phosphorus oxychloride, or phosphorus oxychloride and N, the dinethylformamide mixed solvent, under 100～110 ℃, reflux after 90～135 minutes, in reaction solution impouring frozen water, gained solid organic solvent extraction and recrystallization, promptly make the formula I compound of white solid, wherein, in the formula I compound: R
1, R
2Be hydrogen atom; Yield is not less than 90%, and reaction formula is as follows:
In above-mentioned steps 1, during preparation formula III compound, the concentration of hydrochloric acid soln is 2～4mol/L, and the ratio of the amount of substance of formula II compound and oxalic acid diethyl ester (mol) is 1.0: 1.0～1.1; The reflux temperature of reaction is 70～80 ℃; The reaction times of reaction is 90～120 minutes.
In above-mentioned steps 2, the R in preparation formula IV compound
1, R
2One is hydrogen atom, when another is nitro, nitrating agent is saltpetre and the vitriol oil or trifluoroacetic acid, and wherein the consumption of the vitriol oil is 1000～1100 milliliters with respect to 1 mole of formula III compound, and the ratio of formula III compound and saltpetre amount of substance (mol) is 1.0: 1.0.
In above-mentioned steps 2, the R in preparation formula IV compound
1, R
2When being nitro, nitrating agent is saltpetre and the vitriol oil or trifluoroacetic acid, and wherein the consumption of the vitriol oil is 1000～1100 milliliters with respect to 1 mole of formula III compound, and the ratio of formula III compound and saltpetre amount of substance (mol) is 1.0: 2.0～2.1.
In above-mentioned steps 3 chlorination reactions, the R in formula I compound
1, R
2One is hydrogen atom, and when another was nitro, the ratio of its Chinese style IV compound and phosphorus oxychloride amount of substance (mol) was 1.0: 12.0～16.0, N, and the consumption of dinethylformamide is 180～200 milliliters with respect to 1 mole of formula IV compound.
In above-mentioned steps 3 chlorination reactions, the R in formula I compound
1, R
2During for nitro, the ratio of its Chinese style IV compound and phosphorus oxychloride amount of substance (mol) is 1.0: 8.0～10.0, N, and the consumption of dinethylformamide is 160～170 milliliters with respect to 1 mole of formula IV compound.
In above-mentioned steps 4 chlorination reactions, wherein the ratio of formula III compound and phosphorus oxychloride amount of substance (mol) is 1.0: 9.0～13.0, N, and the consumption of dinethylformamide is 50～80 milliliters with respect to 1 mole of formula III compound.
The positively effect that the present invention produces owing to said synthesis route is conspicuous, i.e. the characteristics that the present invention has are: with cheap, the O-Phenylene Diamine that is easy to get as starting raw material; Adopt phosphorus oxychloride and N first, the method for dinethylformamide mixed solvent is converted into target compound formula I compound with the IV compound; With the recrystallization solvent of alternative chloroforms such as dehydrated alcohol, propyl carbinol, overcome the shortcoming that chloroform is volatile, toxicity is big as formula I compound.
Experimental result shows: this route not only yield is higher, and cost is lower, easy and simple to handle, has industrialized prospect simultaneously.
Embodiment
Following embodiment can further explain the present invention:
Embodiment 1 ring-closure reaction example
In the 100ml there-necked flask, add formula II compound 5.4g, oxalic acid diethyl ester 6.8ml and 4molL
-1Hydrochloric acid 25ml, reflux 90 minutes.After the cooling, obtain the needle-like crystal of off-white color, suction filtration, washing obtains the needle-like crystal of white, after the drying, obtain 2,3 (1H, 4H)-Quinoxalinediones (formula III compound) 6.6g, yield 82%, mp＞300 ℃.
Embodiment 2 nitration reaction examples 1
In 50ml single port flask, add formula III compound 4.86g and 96% sulfuric acid 38ml, cryosel is bathed and is stirred, and is cooled to 0 ℃, add saltpetre 3.0g, reaction solution is maintained 0 ℃, stir after 30 minutes, remove cryosel and bathe, stirring at room 4 hours is poured reaction solution in the frozen water of 300ml stirring then, generate yellow powder shape solid, suction filtration, filter cake distilled water wash, after the oven dry, obtain 6-nitro-2,3 (1H, 4H)-and Quinoxalinediones 5.9g, yield 99%, mp＞300 ℃.MS：208(M-1)。
Embodiment 3 nitration reaction examples 2
In 50ml single port flask, add formula III compound 4.86g and 96% sulfuric acid 32ml, cryosel is bathed and is stirred, and is cooled to 0 ℃, add saltpetre 6.0g, reaction solution is maintained 0 ℃, stir after 30 minutes, remove cryosel and bathe, stirring at room 4 hours is poured reaction solution in the frozen water of 300ml stirring then, generates yellow powder shape solid, suction filtration, the filter cake distilled water wash is after the oven dry, obtain 6,7-dinitrobenzene-2,3 (1H, 4H)-and Quinoxalinediones 5.9g, yield 78%, mp＞300 ℃.MS：252(M)。
Embodiment 4 chlorination reaction examples 1
In the 50ml there-necked flask, and adding 2,3 (1H, 4H)-Quinoxalinediones 16.2g, phosphorus oxychloride 120ml and N, dinethylformamide 5ml, oil bath, 100 ℃ of backflows are cooled off after about 1 hour, and the adularescent solid is separated out.Reaction solution is transferred in the 100ml frozen water, generated the acicular solid of a large amount of off-white colors, suction filtration, the filter cake distilled water wash after the drying, obtains white solid 2,3-dichloro-quinoxaline 18.81g, yield 92.8%, 147～149 ℃ of mp.MS：198(M-1)。
Embodiment 5 chlorination reaction examples 2
In the 50ml there-necked flask, and adding 6-nitro-2,3 (1H, 4H)-Quinoxalinediones 2.1g, phosphorus oxychloride 16ml and N, dinethylformamide 2ml, oil bath, 100 ℃ of backflows are cooled off after about 2 hours, and the adularescent solid is separated out.Reaction solution is transferred in the 100ml frozen water, generated the acicular solid of a large amount of off-white colors, suction filtration, the filter cake distilled water wash, after the drying, with chloroform dissolving, suction filtration, steam the chloroform that removes in the filtrate, drying obtains white solid 6-nitro-2,3-dichloro-quinoxaline 2.35g, yield 95.3%, 147～149 ℃ of mp.Use the propyl carbinol recrystallization, mp150～152 ℃.MS：243(M-1)。
Embodiment 6 chlorination reaction examples 3
In the 50ml there-necked flask, add 6,7-dinitrobenzene-2,3 (1H, 4H)-Quinoxalinediones 15.0g, phosphorus oxychloride 45ml and N, dinethylformamide 10ml, oil bath, behind 100 ℃ of about 2h that reflux, cooling, the adularescent solid is separated out.Reaction solution is transferred in the 500ml frozen water, generated the acicular solid of a large amount of off-white colors, suction filtration, the filter cake distilled water wash after the drying, dissolves with chloroform, suction filtration boils off chloroform, drying, obtain white solid 6,7-dinitrobenzene-2,3-dichloro-quinoxaline 13.7g, yield 80.6%, 212～214 ℃ of mp, MS:288 (M-1).
Claims (8)
1. the method for preparation I compound, formula I is:
R
1, R
2Can be hydrogen atom; It perhaps is nitro; Perhaps one is hydrogen atom, and another is a nitro;
This method comprises the steps:
1), ring-closure reaction: in hydrochloric acid soln, O-Phenylene Diamine and oxalic acid diethyl ester under 70～80 ℃, reacted 90～120 minutes, made the formula III compound.Reaction formula is as follows:
2), nitration reaction: the formula III compound and the vitriol oil are cooled to 0 ℃, add nitrating agent, kept 20～40 minutes, at room temperature react 3～5 hours again after, reaction solution is poured in the frozen water, separate out solid, be formula IV compound, reaction formula is as follows:
In the formula IV compound: R
1, R
2Be nitro, perhaps one is to be hydrogen atom, and another is a nitro.
3), chlorination reaction: formula IV compound is added phosphorus oxychloride, or phosphorus oxychloride and N, the dinethylformamide mixed solvent refluxes down at 100～110 ℃, in formula IV compound: R
1, R
2During for nitro, the reaction times is 120～135 minutes; Or in formula IV compound: R
1, R
2One is to be hydrogen atom, and when another was nitro, the reaction times was 90～120 minutes, and in reaction solution impouring frozen water, the gained solid promptly makes the formula I compound of white solid with organic solvent extraction and recrystallization, and yield is not less than 80%, and reaction formula is as follows:
Or 4), chlorination reaction: the formula III compound is added phosphorus oxychloride, or phosphorus oxychloride and N, the dinethylformamide mixed solvent, under 100～110 ℃, reflux after 90～135 minutes, in reaction solution impouring frozen water, gained solid organic solvent extraction and recrystallization, promptly make the formula I compound of white solid, wherein, in the formula I compound: R
1, R
2Be hydrogen atom; Yield is not less than 90%, and reaction formula is as follows:
2. by the described method of claim 1, it is characterized in that: in above-mentioned steps 1, during preparation formula III compound, the concentration of hydrochloric acid soln is 2～4mol/L, and the ratio of the amount of substance of formula II compound and oxalic acid diethyl ester (mol) is 1.0: 1.0～1.1; The reflux temperature of reaction is 70～80 ℃; The reaction times of reaction is 90～120 minutes.
3. by the described method of claim 1, it is characterized in that: in above-mentioned steps 2, the R in preparation formula IV compound
1, R
2One is hydrogen atom, when another is nitro, nitrating agent is saltpetre and the vitriol oil or trifluoroacetic acid, and wherein the consumption of the vitriol oil is 1000～1100 milliliters with respect to 1 mole of formula III compound, and the ratio of formula III compound and saltpetre amount of substance (mol) is 1.0: 1.0.
4. by the described method of claim 1, it is characterized in that: in above-mentioned steps 2, the R in preparation formula IV compound
1, R
2When being nitro, nitrating agent is saltpetre and the vitriol oil or trifluoroacetic acid, and wherein the consumption of the vitriol oil is 1000～1100 milliliters with respect to 1 mole of formula III compound, and the ratio of formula III compound and saltpetre amount of substance (mol) is 1.0: 2.0～2.1.
5. by the described method of claim 1, it is characterized in that: in above-mentioned steps 3 chlorination reactions, the R in formula I compound
1, R
2One is hydrogen atom, and when another was nitro, the ratio of its Chinese style IV compound and phosphorus oxychloride amount of substance (mol) was 1.0: 12.0～16.0, N, and the consumption of dinethylformamide is 180～200 milliliters with respect to 1 mole of formula IV compound.
6. by the described method of claim 1, it is characterized in that: in above-mentioned steps 3 chlorination reactions, the R in formula I compound
1, R
2During for nitro, the ratio of its Chinese style IV compound and phosphorus oxychloride amount of substance (mol) is 1.0: 8.0～10.0, and the consumption of N.N-dimethyl formamide is 160～170 milliliters with respect to 1 mole of formula IV compound.
7. by the described method of claim 1, it is characterized in that: in above-mentioned steps 4 chlorination reactions, wherein the ratio of formula III compound and phosphorus oxychloride amount of substance (mol) is 1.0: 9.0～13.0, N, and the consumption of dinethylformamide is 50～80 milliliters with respect to 1 mole of formula III compound.
8. by the described method of claim 1, it is characterized in that: organic reagent is phosgene or trichloromethane; Recrystallization solvent is dehydrated alcohol or propyl carbinol.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875482A (en) * | 2012-10-15 | 2013-01-16 | 盛世泰科生物医药技术(苏州)有限公司 | Method for synthesizing decahydroquinoxaline |
| CN103304584A (en) * | 2012-03-06 | 2013-09-18 | 南京大学 | 2-hydrazone-thiazolo[4,5-b]quinoxaline compounds, and preparation method and purpose thereof |
| CN103965122A (en) * | 2014-03-18 | 2014-08-06 | 浙江工业大学 | Nitration method of quinoxaline substituted alkane |
| CN105582477A (en) * | 2016-02-29 | 2016-05-18 | 崔志友 | Traditional Chinese medicine ointment for treating bone diseases |
| CN108558885A (en) * | 2018-05-21 | 2018-09-21 | 兰州大学 | A kind of includes the synthetic method of the dihydro azepine of adjacent diaminophenazine structure and benzene-like compounds |
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2006
- 2006-11-09 CN CNA2006100545827A patent/CN1958578A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304584A (en) * | 2012-03-06 | 2013-09-18 | 南京大学 | 2-hydrazone-thiazolo[4,5-b]quinoxaline compounds, and preparation method and purpose thereof |
| CN102875482A (en) * | 2012-10-15 | 2013-01-16 | 盛世泰科生物医药技术(苏州)有限公司 | Method for synthesizing decahydroquinoxaline |
| CN103965122A (en) * | 2014-03-18 | 2014-08-06 | 浙江工业大学 | Nitration method of quinoxaline substituted alkane |
| CN105582477A (en) * | 2016-02-29 | 2016-05-18 | 崔志友 | Traditional Chinese medicine ointment for treating bone diseases |
| CN108558885A (en) * | 2018-05-21 | 2018-09-21 | 兰州大学 | A kind of includes the synthetic method of the dihydro azepine of adjacent diaminophenazine structure and benzene-like compounds |
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