CN101235012A - Method for preparing 6-methoxy-1,2,3,9-4H-carbazol-4-one - Google Patents
Method for preparing 6-methoxy-1,2,3,9-4H-carbazol-4-one Download PDFInfo
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- CN101235012A CN101235012A CNA2008100341532A CN200810034153A CN101235012A CN 101235012 A CN101235012 A CN 101235012A CN A2008100341532 A CNA2008100341532 A CN A2008100341532A CN 200810034153 A CN200810034153 A CN 200810034153A CN 101235012 A CN101235012 A CN 101235012A
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Abstract
The invention relates to a preparation method of 6-methoxamine-1, 2, 3, 9-tetrahydrochysene-4H-carbazole-4-ketone (I) represented as formula at right, belonging to drug synthesis technical field. The invention utilizes 3-[2-(4-methoxy phenyl) hydrazone] cyclohexyl-1-enol (II) or relative hydrochlorate (III) to process Fischer indole cyclization reaction in diphenyl ether solvent to obtain a compound (I), wherein the hydrochlorate (III) of compound II is prepared by condensing 4-methoxy phenyl hydrazine hydrochloride (IV) and 1, 3-cyclohexane dione (V) in the catalysis of acid. The invention uses industrial product as material, with low production cost, simple process, flexible operation and high synthesis yield, thus is suitable for industrial production. The product has high product purity, which can be used as key synthesis intermediate for drug research.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to 6-methoxyl group-1,2,3, the preparation method of 9-tetrahydrochysene-4H-carbazole-4-ketone (I).
Background technology
6-methoxyl group-1,2,3,9-tetrahydrochysene-4H-carbazole-4-ketone (I) is the key intermediate of preparation antiemetic ondansetron derivative, and also be preparation carbazoles maincenter tranquilizer and 5-hydroxytryptamine receptor antagonist key intermediate (WO0117963, US3634420, US4725615).
It is raw material that prior art discloses with 4-methoxyl group hydrazinobenzene hydrochloride salt and hydroresorcinol, makes the main synthetic method of above-mentioned formula (I) compound through Fischer indoles ring-closure reaction.Described Fischer indoles ring-closure reaction can be that adding concentrated hydrochloric acid back flow reaction can make formula (I) compound (Chem Pharm Bull without separating directly after refluxing in ethanol, 1983,31 (8): 2652-2661), yield 33%, the formula that makes (I) compound purity low (purple crystal).U.S. Pat 4725615 these Fischer indoles ring-closure reactions of report can directly carry out in pure water mixed solution, but its yield also only is 39%.International publication WO0117963 also discloses this Fischer indoles ring-closure reaction can carry out in reflux in toluene, reaction finishes the back concentrated solvent, gained residue thing grinds the formula that can obtain (I) compound in methylene chloride-methanol, yield can reach 65%, but the used solvent of this method, as toluene, toxicity is bigger, and when adopting the industrial goods raw material, grinds in methylene chloride-methanol that to obtain formula (I) compound purity low, and used grinding purification process is wayward, can't reach the expection yield.
U.S. Pat 3634420 discloses the method for another kind of synthesis type (I) compound: with (trifluoromethyl) cyclohexyl-2,5-diene-1,4-diketone and 3-aminocyclohexyl-2-ketenes are raw material, through condensation, cyclisation, decarboxylation, the oxygen formula that obtains (I) compound that methylates, this method route is long and yield is low.
Summary of the invention
Technical problem to be solved by this invention is at the synthetic 6-methoxyl group-1,2,3 of above-mentioned prior art, the existing defective of method of 9-tetrahydrochysene-4H-carbazole-4-ketone (I), provide a kind of easy and simple to handle, product is easy to purifying, be suitable for the method for suitability for industrialized production.
The invention provides a kind of by following reaction formula 1 preparation 6-methoxyl group-1,2,3, the method for 9-tetrahydrochysene-4H-carbazole-4-ketone (I), comprising 3-[2-(4-p-methoxy-phenyl) hydrazone] Fischer indoles ring-closure reaction takes place in cyclohexyl-1-enol (II) or its hydrochloride (III) in the phenyl ether solvent
Wherein, described formula II compound or formula III compound are 1: 15～1: 25 with the mass/volume ratio of described phenyl ether solvent, and preferred mass/volume ratio is 1: 18～1: 20; Described temperature of reaction is 120～200 ℃, and preferable reaction temperature is 135～185 ℃.
Raw material that the inventive method adopts is industrial goods.
The compound of formula III described in the inventive method adopts 4-methoxyl group hydrazinobenzene hydrochloride salt (IV) and 1, hydroresorcinol (V) is a raw material, condensation reaction takes place under acid catalysis to be made, described temperature of reaction is-20～40 ℃, wherein said acid can be inorganic proton acid, organic protonic acid or its mixing acid, preferably sulfuric acid, hydrochloric acid, acetic acid or its mixing acid, more preferably acetic acid; Described temperature of reaction is-10～30 ℃, preferred 0～15 ℃, and more preferably 5～10 ℃.
Usually, above-mentioned preparation process is carried out in organic solvent, water or its mixed solvent, and appropriate organic solvent is easy and miscible organic solvent such as acetonitrile, acetone or the alcohol of water, is preferably acetonitrile.
In the present invention, described formula II compound can be obtained through suitable alkaline purification by the III compound, and suitable alkali comprises ammoniacal liquor, organic amine, alkali-metal carbonate, alkali-metal supercarbonate or its mixed base, is preferably ammoniacal liquor, triethylamine, Na
2CO
3, NaHCO
3, K
2CO
3Perhaps KHCO
3
Usually, above-mentioned alkaline purification process can be carried out under cooling, normal temperature or heating condition, and the selection of temperature of reaction and the consumption of alkali have certain influence to alkaline purification, and these all are within those skilled in the art's knowledge category.In the present invention, its alkali purification temp is-20 ℃～60 ℃, preferred-10 ℃～20 ℃; The amount of used alkali can determine that those skilled in the art can easily determine the peak optimization reaction temperature of alkaline purification and suitable alkali consumption by the technique means of this area routine by the pH that measures reaction solution.
The reaction times of above-mentioned each reaction does not all have special qualification, can easily determine by the technique means of this area routine, adopts the thin-layer chromatography method just can monitor reaction end simply, fast as those skilled in the art.
The preparation method of formula I compound provided by the invention, outstanding advantage are the synthesis yield height.Another significant advantage is that the Fischer indoles cyclization reaction conditions that adopts of present method is easy to be controlled, and no matter adopt 3-[2-(4-p-methoxy-phenyl) hydrazone] cyclohexyl-1-enol (II) still its hydrochloride (III) be raw material, this reaction all can be carried out smoothly, makes its operation more flexible.
It is raw material that intermediate formula II compound that the present invention relates to or formula III compound adopt 4-methoxyl group hydrazinobenzene hydrochloride salt and hydroresorcinol cheap and easy to get, and production cost is low; The preparation method of formula I compound provided by the invention adopts the method purified product of recrystallization, and its method is simple, be suitable for suitability for industrialized production, and products obtained therefrom purity height, is suitable for being further used for medicament research and development as crucial synthetic intermediate.
According to the description of foregoing, under the prerequisite that does not break away from basic fundamental thought of the present invention,, the modification and the replacement of various ways can also be arranged to the embodiment of foregoing invention according to ordinary skill knowledge or customary means.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that following examples only are used to illustrate the present invention, and be not used in restriction the present invention.The experimental technique of unreceipted actual conditions in the following example is operated according to normal condition usually.TLC refers to thin-layer chromatography in below describing, and m.p. is a fusing point, and MS is a mass spectrum,
1H-NMR (400MHz, DMSO-d
6) to refer under the 400MHz condition with the deuterated dimethyl sulfoxide be the nucleus magnetic resonance that solvent is measured proton, δ is chemical shift, and its unit is ppm, and J is a coupling constant.Unless explanation is arranged in addition, otherwise umber is considered as parts by weight, per-cent is considered as weight percent.
Embodiment
Embodiment 1 3-[2-(4-p-methoxy-phenyl) hydrazone] cyclohexyl-1-enolate hydrochlorate (III)
(industrial goods 0.132mol), add the 50mL acetonitrile to 4-methoxyl group hydrazinobenzene hydrochloride salt 25.0g, add hydroresorcinol 16.0g (industrial goods, acetonitrile-acetic acid 0.140mol) (50mL/15mL) solution, room temperature reaction, TLC monitoring reaction terminal point.After question response was complete, cooling crystallization filtered, and with the acetonitrile washing, got glassy yellow needle 33.1g after the oven dry, was titled reference compound through differentiating, yield 93.2%.m.p.206-207℃。MS：[M+H]
+233.1。
1HNMR(400MHz，DMSO-d
6)δ：10.47(brs，1H)，8.08(brs，1H)，6.83-6.70(m，4H)，5.58(s，1H)，3.67(s，3H)，2.57(t，2H，J＝6.0Hz)，2.34(t，2H，J＝6.0Hz)，1.90(m，2H)。
Titled reference compound also can prepare by the following method:
Alternative method one: (industrial goods 0.494mol), add 70mL water to 4-methoxyl group hydrazinobenzene hydrochloride salt 93.4g, add the glacial acetic acid solution 70mL of hydroresorcinol 60.0g (0.524mol) again, room temperature reaction, TLC monitoring reaction terminal point.Add the 70mL acetonitrile, continue to stir 15min, add the 50mL acetonitrile again, cooling, crystallization, filtration with the acetonitrile washing, get glassy yellow needle 86.7g, yield 65.4% after the oven dry.
Alternative method two: (industrial goods 0.0100mol), add the 10mL acetonitrile to 4-methoxyl group hydrazinobenzene hydrochloride salt 1.90g, add the 5% diluted hydrochloric acid aqueous solution 2.5mL of hydroresorcinol 1.22g (0.0107mol) again, room temperature reaction, TLC monitoring reaction terminal point.After question response was complete, cold analysis, filtration with the acetonitrile washing, got faint yellow solid 1.35g, yield 50.0% after the oven dry.
Alternative method three: (industrial goods 0.0097mmol), add the 10mL acetonitrile to 4-methoxyl group hydrazinobenzene hydrochloride salt 1.83g, add the 5% dilute sulfuric acid aqueous solution 2.2mL of hydroresorcinol 1.18g (0.0103mol) again, room temperature reaction, TLC monitoring reaction terminal point.After question response was complete, cold analysis, filtration with the acetonitrile washing, got faint yellow solid 1.23g, yield 47.3% after the oven dry.
Embodiment 2 3-[2-(4-p-methoxy-phenyl) hydrazone] cyclohexyl-1-enol (II)
3-[2-(4-p-methoxy-phenyl) hydrazone with the described method preparation of embodiment 1] cyclohexyl-1-enolate hydrochlorate 25.0g (0.093mol) adds in the 100mL water, add 10% wet chemical and regulate pH to 7, filter, oven dry, obtain white powder 21.3g, be titled reference compound, yield 98.6% through differentiating.MS：[M+H]
+233.1。
Titled reference compound also can prepare by the following method: with embodiment 1 described method preparation methoxyl group phenylhydrazone hydrochloride 60g (0.223mol) is added in the 500mL water, drip 25% ammoniacal liquor and regulate pH to 7, filter, oven dry, obtain white powder 50g, yield 98.0%
Embodiment 3 6-methoxyl groups-1,2,3,9-tetrahydrochysene-4H-carbazole-4-ketone (I)
20mL phenyl ether (industrial goods), be heated to liquid slightly, 3-[2-(4-p-methoxy-phenyl) hydrazone that adds embodiment 1 described method preparation then] cyclohexyl-1-enolate hydrochlorate 1.0g (0.0037mol), 135～140 ℃ of following stirring reactions, TLC shows the monitoring reaction terminal point.When being cooled to 40～60 ℃, filtering fast and obtain crude product, ethyl alcohol recrystallization gets off-white color crystallization 490mg, is titled reference compound, yield 61.3% through differentiating.m.p.266-267℃。ESI-MS：[M+H]
+216.1。
1HNMR(400MHz，DMSO-d
6)δ：11.72(brs，1H)，7.43(d，1H，J＝2.3Hz)，7.26(d，1H，J＝8.2Hz)，6.77-6.75(dd，1H，J
1＝8.2Hz，J
2＝2.3Hz)，3.74(s，3H)，2.91(t，2H，J＝6.3Hz)，2.40(t，2H，J＝6.3Hz)，2.08(m，2H)。
Titled reference compound also can prepare by the following method:
Alternative method one: 40mL phenyl ether (industrial goods), be heated to liquid slightly, add 3-[2-(4-p-methoxy-phenyl) hydrazone again according to embodiment 1 described method preparation] cyclohexyl-1-enolate hydrochlorate 2.2g (0.0082mol), 185 ℃ of reactions, TLC monitoring reaction terminal point.When being cooled to 40～60 ℃, filtering fast and obtain crude product, ethyl alcohol recrystallization can get off-white color crystallization 1.0g, is titled reference compound, yield 56.8% through differentiating.
Alternative method two: 90mL phenyl ether (industrial goods), be heated to liquid slightly, add 3-[2-(4-p-methoxy-phenyl) hydrazone again according to embodiment 2 described method preparations] cyclohexyl-1-enol 5.0g (0.0215mol), 165～170 ℃ of reactions, TLC monitoring reaction terminal point.When being cooled to 40～60 ℃, filtering fast and obtain crude product, ethyl alcohol recrystallization can get off-white color crystallization 2.7g, yield 58.3%.
Claims (10)
1. one kind prepares 6-methoxyl group-1,2,3, the method of 9-tetrahydrochysene-4H-carbazole-4-ketone (I) is characterized in that, by following reaction formula 1, comprising 3-[2-(4-p-methoxy-phenyl) hydrazone] cyclohexyl-1-enol (II) or its hydrochloride (III) carry out Fischer indoles ring-closure reaction in the phenyl ether solvent
2. method according to claim 1, wherein said formula II compound or formula III compound are 1: 15～1: 25 with the mass/volume ratio of described phenyl ether solvent, described temperature of reaction is 120～200 ℃.
3. method according to claim 2 is characterized in that described mass/volume ratio is 1: 18～1: 20, and described temperature of reaction is 135～185 ℃.
4. according to the arbitrary described method of claim 1～3, wherein said formula III compound is to adopt 4-methoxyl group hydrazinobenzene hydrochloride salt (IV) and 1, hydroresorcinol (V) is a raw material, condensation reaction takes place under acid catalysis make, and described setting-up point is-20～40 ℃.
5. method according to claim 4, wherein said acid are selected from inorganic proton acid, organic protonic acid or their mixing acid, and described setting-up point is-10～30 ℃.
6. method according to claim 5, wherein said acid are sulfuric acid, hydrochloric acid, acetic acid or its mixing acid, and described temperature of reaction is 0～15 ℃.
7. method according to claim 6, wherein said acid are acetic acid, and described temperature of reaction is 5～10 ℃.
8. according to the arbitrary described method of claim 1～3, wherein said formula II compound is to be made through alkaline purification by the III compound.
9. method according to claim 8, wherein said alkali are selected from ammoniacal liquor, organic amine, alkali-metal carbonate, alkali-metal supercarbonate or its mixed base.
10. method according to claim 9, wherein said alkali is selected from ammoniacal liquor, triethylamine, Na
2CO
3, NaHCO
3, K
2CO
3Or KHCO
3
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478635A (en) * | 2016-08-25 | 2017-03-08 | 西安欧得光电材料有限公司 | A kind of green synthesis method of electroluminescent organic material indole carbazole compound |
| CN110950873A (en) * | 2019-12-10 | 2020-04-03 | 河南大学 | New synthesis method of paludidole |
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2008
- 2008-02-29 CN CN200810034153A patent/CN100584829C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478635A (en) * | 2016-08-25 | 2017-03-08 | 西安欧得光电材料有限公司 | A kind of green synthesis method of electroluminescent organic material indole carbazole compound |
| CN106478635B (en) * | 2016-08-25 | 2018-09-25 | 西安欧得光电材料有限公司 | A kind of green synthesis method of electroluminescent organic material indole carbazole compound |
| CN110950873A (en) * | 2019-12-10 | 2020-04-03 | 河南大学 | New synthesis method of paludidole |
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