CN115677561A - 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone and synthesis method thereof - Google Patents
1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone and synthesis method thereof Download PDFInfo
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
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- 238000010438 heat treatment Methods 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- SFLXUZPXEWWQNH-UHFFFAOYSA-K tetrabutylazanium;tribromide Chemical compound [Br-].[Br-].[Br-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC SFLXUZPXEWWQNH-UHFFFAOYSA-K 0.000 claims abstract description 10
- 239000000706 filtrate Substances 0.000 claims abstract description 7
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- WGNNILPYHCKCFF-UHFFFAOYSA-N 2-chloro-n-methylaniline Chemical group CNC1=CC=CC=C1Cl WGNNILPYHCKCFF-UHFFFAOYSA-N 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- SMVIAQFTVWDWDS-UHFFFAOYSA-N 2-bromo-n-methylaniline Chemical compound CNC1=CC=CC=C1Br SMVIAQFTVWDWDS-UHFFFAOYSA-N 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- 229940045803 cuprous chloride Drugs 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- ZBFZXENHYIJZGA-UHFFFAOYSA-N 2,3,4,4a-tetrahydrocarbazol-1-one Chemical compound C1=CC=C2C3CCCC(=O)C3=NC2=C1 ZBFZXENHYIJZGA-UHFFFAOYSA-N 0.000 description 11
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
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- -1 1,2,3, 9-tetrahydro-methyl { (2-methylimidazol-1-yl) methyl } -4-oxocarbazole hydrochloride Chemical compound 0.000 description 2
- MKBLHFILKIKSQM-UHFFFAOYSA-N 9-methyl-3-[(2-methyl-1h-imidazol-3-ium-3-yl)methyl]-2,3-dihydro-1h-carbazol-4-one;chloride Chemical compound Cl.CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 MKBLHFILKIKSQM-UHFFFAOYSA-N 0.000 description 2
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
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- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone and a synthesis method thereof, which comprises the steps of adding 2-cyclohexene-1-ketone into a reaction bottle with a stirrer and a thermometer, adding tetrabutyl ammonium tribromide in batches, heating, stirring, reacting, sequentially adding 2-halogeno-N-methylaniline, alkali and a catalyst into the reaction bottle, stirring, reacting at an increased temperature, tracking and reacting by TLC, cooling after the reaction is finished, filtering, distilling the filtrate under reduced pressure, distilling off redundant 2-halogeno-N-methylaniline, washing the residual solid with water for multiple times, and obtaining the 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone. Compared with the prior art, the 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone prepared by the method has high purity and high yield, the yield can reach more than 93 percent, the purity is more than 99 percent, and the method is suitable for large-scale production.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone and a synthesis method thereof.
Background
Ondansetron hydrochloride, having the chemical name 1,2,3, 9-tetrahydro-methyl { (2-methylimidazol-1-yl) methyl } -4-oxocarbazole hydrochloride, is an alternative 5-hydroxytryptamine 3 (5-HT) 3 ) Receptor antagonists which can be prepared byAntagonizing 5-HT in peripheral vagal nerve endings and central chemosensory areas 3 The receptor can block the vomiting reflex caused by the fact that the factor of chemotherapy and operation promotes the small intestine pheochromocyte to release 5-hydroxytryptamine and excite the coma to pass through the afferent nerve.
At present, the tetrahydrocarbazolone (1) or the 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone (2) is a key raw material for preparing ondansetron hydrochloride in industrial production, and the quality of a product directly determines the quality of a final product, but at present, the synthesis process of the tetrahydrocarbazolone or the 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone is extensive in process, low in yield and poor in quality of the synthesized product, and the subsequent application range of the product is limited.
Chinese patent application No. CN201710375453.6 discloses a synthesis method of tetrahydrocarbazolone, and the related synthesis route is shown as the following formula:
the synthesis route takes 1, 3-cyclohexanedione and aniline as raw materials, the 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone is obtained through two-step reaction, the 1,3, 4-tetrahydro-9-methyl-4H-carbazolone is obtained through methylation reaction of the tetrahydro-carbazolone, raw and auxiliary materials used in the reaction comprise more than ten kinds of aluminum oxide, toluene, palladium acetate and the like, the types of the raw and auxiliary materials are multiple, the price of a catalyst is high, a silica gel column is needed for obtaining the tetrahydro-carbazolone, the synthesis cost is increased, and the industrialization process is influenced.
Disclosure of Invention
The invention aims to solve the problems that the prior art has various types of raw and auxiliary materials for synthesizing 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone, expensive catalysts and the need of passing through a silica gel column to obtain a target product, and provides the 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone and a synthesis method thereof.
In order to achieve the purpose, the invention is implemented according to the following technical scheme:
the first purpose of the invention is to provide a method for synthesizing 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone, which comprises the following steps:
s1, taking 2-cyclohexene-1-ketone and tetrabutylammonium tribromide in a weight ratio of 1: 1.6-2, adding the 2-cyclohexene-1-ketone into a reaction bottle with a stirrer and a thermometer, adding the tetrabutylammonium tribromide into the reaction bottle for 3-5 times, heating to 75-85 ℃, and stirring for reaction for 2-5 hours;
s2, sequentially adding 3-5 times of 2-halogenated-N-methylaniline by weight of 2-cyclohexene-1-ketone, 1.1-1.7 times of alkali by weight of 2-cyclohexene-1-ketone and 0.002-0.012 times of catalyst by weight of 2-cyclohexene-1-ketone into a reaction bottle of the reaction product obtained in the step S1, heating to 110-120 ℃, stirring for reaction for 3-4H, carrying out TLC tracking reaction, cooling after the reaction is finished, filtering, distilling the filtrate under reduced pressure, evaporating redundant 2-halogenated-N-methylaniline, washing the residual solid with water for at least 3 times to obtain 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone.
As a preferred technical scheme of the invention, the alkali is potassium carbonate or sodium carbonate.
As a preferred technical scheme of the invention, the 2-halogenated-N-methylaniline is 2-chloro-N-methylaniline or 2-bromo-N-methylaniline.
As a preferable technical scheme of the invention, the catalyst is one of cuprous chloride, cuprous bromide and cuprous iodide.
The second purpose of the invention is to provide 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone synthesized by the synthesis method.
Compared with the prior art, the invention has the following beneficial effects:
1. according to the invention, tetrabutylammonium tribromide is used as a brominating reagent, and can be directly dissolved in raw materials to participate in reaction after being heated, no additional solvent is required to be added in the reaction, so that the method is environment-friendly and efficient, the ammonium salt after the reaction can be directly used as an acid-binding agent in the next step without treatment, the cost is greatly saved, and the discharge of three wastes is reduced;
2. the adding amount of the 2-bromo (chloro) -N-methylaniline is excessive, and the excessive amount can ensure that the compound 3-bromo-cyclohexane-1-ketone can be completely reacted; secondly, the 2-bromine (chlorine) -N-methylaniline is alkaline and can be used as an acid-binding agent to neutralize HBr (HCl) generated in the reaction, thereby being beneficial to the full reaction; thirdly, the excessive 2-bromine (chlorine) -N-methylaniline can be used as a solvent, thereby avoiding the increase of cost and secondary pollution caused by the use of other solvents in a reaction system;
3. the synthesis method has the advantages of easily available raw materials, convenient operation and mild reaction conditions, and the prepared 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone has high purity and yield, the yield can reach more than 93 percent and the purity can reach more than 99 percent, thereby being suitable for large-scale production.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone.
FIG. 2 is a nuclear magnetic carbon spectrum of 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. The specific embodiments described herein are merely illustrative of the invention and do not delimit the invention.
The reagents and starting materials used in the following examples are commercially available unless otherwise specified, and their specific sources are not described in detail.
The synthetic route of the 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone is as follows:
the synthesis of the present invention is illustrated in detail by the specific examples below.
Example 1
Adding 1kg of 2-cyclohexene-1-ketone into a reaction bottle with a stirrer and a thermometer, adding 1.6kg of tetrabutylammonium tribromide in three batches, heating to 75 ℃, stirring for reaction for 2 hours, then sequentially adding 3kg of 2-chloro-N-methylaniline, 1.1kg of potassium carbonate and 0.002kg of cuprous chloride as a catalyst into the reaction bottle, heating to 110 ℃, stirring for reaction for 3 hours, tracking the reaction by TLC, filtering after cooling after the reaction is finished, distilling the filtrate under reduced pressure, distilling off the redundant filtrate2-chloro-N-methylaniline, and the remaining solid was washed with water 3 times to give 1.83kg of 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone. In order to determine the molecular structure of the prepared 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone, the nuclear magnetic resonance detection is carried out on the prepared 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone, and the nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum are respectively shown in figures 1 and 2, and the following results can be known from figures 1 and 2: m.p.192.7-194.1 deg.c; 1 H NMR(300MHz，DMSO-d 6 )δ:8.06～7.99(m，1H，-Ar-H)，7.61～7.46(m， 1H，-Ar-H)，7.38～7.09(m，2H，-Ar-H)，3.70(s，3H，-CH 3 )，2.96(t，J＝6.0 Hz，2H，-CH 2 -)，2.39(t，J＝5.8Hz，2H，-CH 2 -)，2.17～2.01(m，2H，-CH 2 -)； 13 C NMR(75MHz，DMSO-d 6 )δ：196.08，168.48，143.20，123.37，121.91，121.73， 119.78，119.56，110.97，39.12，30.57，22.29；HR(ESI)MS(m/z)：[M+H] + ：200.0993。
by calculation, the yield of the 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone actually obtained in the example/the theoretically obtained compound weight ratio is 88.3%, and the HPLC purity is 97.5% by HPLC analysis.
Example 2
Adding 1kg of 2-cyclohexene-1-ketone into a reaction bottle with a stirrer and a thermometer, adding 1.8kg of tetrabutylammonium tribromide in three batches, heating to 80 ℃, stirring for reaction for 3 hours, then sequentially adding 4kg of 2-bromo-N-methylaniline, 1.5kg of potassium carbonate and 0.009kg of cuprous bromide catalyst into the reaction bottle, heating to 115 ℃, stirring for reaction for 4 hours, tracking and reacting by TLC, cooling after the reaction is finished, filtering, distilling the filtrate under reduced pressure, evaporating redundant 2-bromo-N-methylaniline, washing the residual solid with water for 4 times to obtain 1.93kg of 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone, calculating to obtain the weight ratio of 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone actually obtained in the embodiment to the weight of the theoretically obtained compound, namely the yield is 93.2%, and obtaining the purity of HPLC 99.1% by high performance liquid chromatography analysis.
Example 3
Adding 1kg of 2-cyclohexene-1-ketone into a reaction bottle with a stirrer and a thermometer, adding 2.0kg of tetrabutylammonium tribromide in five batches, heating to 85 ℃, stirring for reaction for 5 hours, then sequentially adding 5kg of 2-chloro-N-methylaniline, 1.7kg of sodium carbonate and 0.012kg of cuprous iodide serving as a catalyst into the reaction bottle, heating to 120 ℃, stirring for reaction for 3.5 hours, tracking and reacting by TLC, cooling after the reaction is finished, filtering, distilling the filtrate under reduced pressure, distilling off redundant 2-halogeno-N-methylaniline, washing the residual solid with water for 5 times to obtain 1.88kg of 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone, wherein the weight ratio of the 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone actually obtained in the embodiment to the weight of the theoretically obtained compound is calculated, namely the yield is 90.7%, and the HPLC purity is 98.4% by high performance liquid chromatography analysis.
Example 4
Adding 1kg of 2-cyclohexene-1-ketone into a reaction bottle with a stirrer and a thermometer, adding 1.8kg of tetrabutylammonium tribromide in four batches, heating to 80 ℃, stirring for reaction for 4 hours, then sequentially adding 4kg of 2-chloro-N-methylaniline, 1.5kg of sodium carbonate and 0.009kg of cuprous chloride catalyst into the reaction bottle, heating to 110 ℃, stirring for reaction for 3 hours, tracking and reacting by TLC, filtering after the reaction is finished and cooled, distilling the filtrate under reduced pressure, evaporating redundant 2-chloro-N-methylaniline, washing the residual solid for 6 times by using water to obtain 1.85kg of 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone, calculating to obtain the weight ratio of the 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone actually obtained in the embodiment to the weight of the theoretically obtained compound, namely the yield of 89.2%, and obtaining the HPLC purity of 98.1% by high performance liquid chromatography analysis.
The technical solution of the present invention is not limited to the above-mentioned specific embodiments, and all technical modifications made according to the technical solution of the present invention fall within the protection scope of the present invention.
Claims (5)
1. A method for synthesizing 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone is characterized by comprising the following steps:
s1, taking 2-cyclohexene-1-ketone and tetrabutylammonium tribromide in a weight ratio of 1: 1.6-2, adding the 2-cyclohexene-1-ketone into a reaction bottle with a stirrer and a thermometer, adding the tetrabutylammonium tribromide into the reaction bottle for multiple times, heating to 75-85 ℃, and stirring for reaction for 2-5 hours;
s2, sequentially adding 3-5 times of 2-halogenated-N-methylaniline by weight of 2-cyclohexene-1-ketone, 1.1-1.7 times of alkali by weight of 2-cyclohexene-1-ketone and 0.002-0.012 times of catalyst by weight of 2-cyclohexene-1-ketone into a reaction bottle of the reaction product obtained in the step S1, heating to 110-120 ℃, stirring for reaction for 3-4H, carrying out TLC tracking reaction, cooling after the reaction is finished, filtering, distilling the filtrate under reduced pressure, evaporating redundant 2-halogenated-N-methylaniline, washing the residual solid with water for at least three times to obtain 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone.
2. The method of synthesizing 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone according to claim 1, wherein: the alkali is potassium carbonate or sodium carbonate.
3. The method of synthesizing 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone according to claim 1, wherein: the 2-halogenated-N-methylaniline is 2-chloro-N-methylaniline or 2-bromo-N-methylaniline.
4. The method of synthesizing 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone according to claim 1, wherein: the catalyst is one of cuprous chloride, cuprous bromide and cuprous iodide.
5. 1,2,3, 4-tetrahydro-9-methyl-4H-carbazolone synthesized according to the method of any one of claims 1 to 4.
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| CN102464604A (en) * | 2010-11-09 | 2012-05-23 | 哈尔滨理工大学 | Production method of 1,2,3,4-tetrahydro-9-methylcarbazol-4-one |
| CN102850259A (en) * | 2012-09-21 | 2013-01-02 | 天津狄克特科技有限公司 | Preparation method for 6-halogen substituted-1,2,3,4-terahydrocarbazole intermediate of anti-hepatitis c drugs |
| CN103497144A (en) * | 2013-10-01 | 2014-01-08 | 迪沙药业集团山东迪沙药业有限公司 | Preparation method of carbazol ketone tetrahydride |
| CN107235891A (en) * | 2017-05-24 | 2017-10-10 | 北京八亿时空液晶科技股份有限公司 | A kind of preparation method of 4 bromine carbazole |
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