CN103086951B - The preparation method of tetrahydro carbazole - Google Patents
The preparation method of tetrahydro carbazole Download PDFInfo
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- CN103086951B CN103086951B CN201310044311.3A CN201310044311A CN103086951B CN 103086951 B CN103086951 B CN 103086951B CN 201310044311 A CN201310044311 A CN 201310044311A CN 103086951 B CN103086951 B CN 103086951B
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- XKLNOVWDVMWTOB-UHFFFAOYSA-N C(CC1)Cc2c1[nH]c1ccccc21 Chemical compound C(CC1)Cc2c1[nH]c1ccccc21 XKLNOVWDVMWTOB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a kind of preparation method of tetrahydro carbazole, pimelinketone and methanol/ethanol or the mixing solutions of the two are mixed, reflux, passes into dry HCl gas as catalyzer, slowly add phenylhydrazine and methanol/ethanol or the mixing solutions of the two again, continue backflow; After reaction terminates, cooling reaction solution, namely product slowly separates out with crystallite form from methanol/ethanol or the two mixing solutions, adding with the mass ratio of methanol/ethanol or the two mixing solutions is again the distilled water of 1:0.8 ~ 1:1.5, further precipitation product, filter and distilled water wash extremely neutrality, drying can obtain high purity tetrahydro carbazole product; The mass ratio of described phenylhydrazine and methanol/ethanol or the mixing solutions of the two is 1:5 ~ 10; Described phenylhydrazine and the mass ratio of pimelinketone are 1:1.1 ~ 1.5.The present invention, has that technique is simple, economical and convenient, and reaction conditions is gentle, and the reaction times is shorter, the advantages such as product yield and purity is high, environmental protection.
Description
Technical field
The present invention relates to the heterogeneous ring compound containing a nitrogen-atoms, is a kind of preparation method of tetrahydrocarbazole compound specifically.
Background technology
1,2,3,4-tetrahydro carbazole and derivative thereof are medical and very important intermediate in chemical field, as
n-methyl tetrahydro carbazole is the important intermediate of the 5-hydroxytryptamine receptor antagonist ondansetron of synthesis highly selective, and 2-amino-tetrahydro carbazole-propionic acid is thromboxane A
2the key intermediate of receptor antagonist Ramatroban, 1,2,3,4-tetrahydro carbazole can synthesize carbazole by Raney-Ni catalytic dehydrogenation, and carbazole is intermediate important in fine chemicals, can be widely used in the different field such as pigment, dyestuff, plastics, agricultural chemicals, medicine and luminescent material, especially be used for manufacturing para-dye and high-grade pigment dyestuff, therefore the research of tetrahydro carbazole compou nd synthesis and purification process had very important significance.
Method about tetrahydrobiopterin synthesis carbazole has: (1) indoles, aldehydes or ketones and butylmaleimide are the Diels-Alder synthesis method of raw material, (2) Fisher indole synthesis, (3) hydrogen aromatization reaction in the molecule of the alkenyl substituted indoles of metal catalytic, (4) Borsche synthesis method etc.The while that wherein Borsche method being current tetrahydrobiopterin synthesis carbazole, be also one of method of synthesis carbazole most industrial prospect, its synthetic route is as follows:
Be condensed into hydrazone with phenylhydrazine and pimelinketone for raw material, be then cyclized into tetrahydro carbazole in acid condition, tetrahydro carbazole dehydrogenation under the effect of catalyzer can obtain carbazole product.With Borsche method synthesis carbazole and derivative thereof, the purity of intermediate tetrahydro carbazole is most important to subsequent catalyst dehydrogenation synthesis carbazole, if not only caused containing impurity, speed of reaction is slow, productive rate reduces, and also easily may cause poisoning of catalyst.
At first to the method for synthesis 1,2,3,4-tetrahydrocarbazole compound carry out studying be Crosby U. Rogers and B. B. Corson (
j. Am. Chem. Soc., 1947,69 (11), 2910-2911), by phenylhydrazine and pimelinketone under the catalysis of acetic acid or hydrochloric acid, one-step synthesis 1,2,3,4-tetrahydro carbazole, but reaction yield is only about 90% and product purity is not high; (dyestuffs industries, 1998,35 (3) such as Yu Majin, 21-22) take phenylhydrazine as raw material, select acetic acid as solvent and catalyzer synthesis 1,2,3,4-tetrahydro carbazole, the productive rate of thick product about 99%, but needs the refinement treatment through activated carbon decolorizing and ethyl alcohol recrystallization, and industrial use acetic acid, to production unit seriously corroded, severe operational environment, environmental pollution is serious; The Ni gentle Hou Qi army in sea (CN 102249983 A) improves production technique, have employed phenylhydrazine/hydrazinobenzene hydrochloride salt and pimelinketone is raw material, be that solvent synthesizes 1 under mineral acid catalysis with water, 2,3,4-tetrahydro carbazole, the productive rate of its thick product is about 98%, but the method uses hydrazinobenzene hydrochloride salt (PhNHNH
2hCl or [PhNHNH
3]
+cl
-) for need during raw material by the HCl all solutions in hydrochloride from, otherwise the transformation efficiency of the efficiency of real reaction and product to reach reported effect, select water to be that solvent is easy to when product is formed form the phenomenons such as double team and caking simultaneously, to further isolation and purification, particularly the crystallization of product makes troubles, production cycle is long, and production cost is high.For this reason, the inventive method proposes a kind of environmental friendliness, yield is high and be easy to purified crystals, can be applicable to the green industrialized production method of 1,2,3,4-tetrahydro carbazole completely.
Summary of the invention
Object of the present invention is exactly for the above-mentioned problems in the prior art, and provides a kind of
The preparation method of the tetrahydro carbazole that economical and convenient, environmental friendliness, productive rate are high.
For realizing above-mentioned purpose of the present invention, the preparation method of tetrahydro carbazole of the present invention by the following technical solutions:
Tetrahydro carbazole compound structure proposed by the invention is shown below.
Its technology and step prepared is: pimelinketone and methanol/ethanol or the mixing solutions of the two are mixed, reflux, passes into dry HCl gas as catalyzer, more slowly adds phenylhydrazine and methanol/ethanol or the mixing solutions of the two, continues backflow.After reaction terminates, cooling reaction solution, namely product slowly separates out with crystallite form from methanol/ethanol or the two mixing solutions, adding with the mass ratio of methanol/ethanol or the two mixing solutions is again the distilled water of 1:0.8 ~ 1:1.5, further precipitation product, filter and distilled water wash extremely neutrality, drying can obtain high purity tetrahydro carbazole product; The mass ratio of described phenylhydrazine and methanol/ethanol or the mixing solutions of the two is 1:5 ~ 10; Described phenylhydrazine and the mass ratio of pimelinketone are 1:1.1 ~ 1.5.
The purity of described phenylhydrazine is between 95% ~ 99.5%.
The mass ratio of described phenylhydrazine and methanol/ethanol or the mixing solutions of the two is excellent with 1:6 ~ 8; Mass ratio the best of described phenylhydrazine and pimelinketone is 1:1.2 ~ 1.4.
Described dry hydrogen chloride gas is obtained by being slowly added drop-wise to by concentrated hydrochloric acid in the vitriol oil, adjusting gas flow voluntarily, now-making-now-using.Concentrated sulfuric acid solution used only need heat remove portion moisture and reusable.
Tetrahydro carbazole compound structure prepared by the present invention is such as formula shown in lower:
The solvent of technique scheme is methanol/ethanol or the mixing solutions of the two, and raw material is phenylhydrazine.
Published document and patented method before the present invention compares, have the following advantages: (1) for raw material with the phenylhydrazine of rather high concentration, improves speed of reaction and yield, shortens the reaction times; (2) adopt the way of now-making-now-using to pass into hydrogen chloride gas more cost-saving than the hydrogen chloride gas directly bought, and avoid steel cylinder to store the danger of hydrogen chloride gas, in addition, the flow velocity metering ratio of hydrogen chloride gas can also be controlled well; (3) adopt dry hydrogen chloride gas to be passed into method in methanol/ethanol solution, greatly can reduce the corrodibility of reaction solution, have good provide protection to production unit; (4) directly can obtain 1,2,3, the 4-tetrahydro carbazole crystal product of purity > 98.6%, not need, through activated carbon decolorizing and ethyl alcohol recrystallization, to decrease post-processing step, greatly reduce production cost; (5) technique is simple, and condition is relatively gentle, productive rate is high, yield > 98%, and product does not need further separation and purification, and the follow-up synthesis directly can carrying out carbazole and derivative thereof is produced.
In a word, scheme of the present invention has that technique is simple, economical and convenient, and reaction conditions is gentle, and the reaction times is shorter, the advantages such as product yield and purity is high, environmental protection.
Accompanying drawing explanation
Fig. 1 is the synthesizer figure that 1,2,3,4-tetrahydro carbazole is prepared in laboratory.
Reference numeral is: 1-there-necked flask, 2-closed tube, 3-there-necked flask, 4-tail gas receiving device, 5-magnetic stirring apparatus, 6-magnetic stirring apparatus, 7-constant pressure funnel, 8-prolong.
Embodiment
For further describing the present invention, below in conjunction with embodiment, for a more detailed description to the preparation method of tetrahydro carbazole of the present invention.
The synthesizer figure that 1,2,3,4-tetrahydro carbazole is prepared in laboratory as shown in Figure 1 finds out, there-necked flask 1 to be placed on magnetic stirring apparatus 5 and to be fixed by iron stand, and there-necked flask 3 to be placed on magnetic stirring apparatus 6 and to be fixed by iron stand; Between there-necked flask 1, there-necked flask 3, be provided with closed tube 2, closed tube 2 is provided with gas meter, tail gas receiving device 4 is connected by rubber hose and there-necked flask 3, and the tail gas produced in there-necked flask 3 is absorbed by tail gas receiving device 4.The volume of there-necked flask 1, there-necked flask 3 is all 500mL.There-necked flask 1 is provided with constant pressure funnel 7, prolong 8, and there-necked flask 3 is provided with constant pressure funnel 9.
Embodiment 1
Put up experimental installation by shown in Fig. 1, in there-necked flask 3, add 54g(0.55mol by constant pressure funnel 9) pimelinketone, 96g(3mol) methyl alcohol, be uniformly mixed by magnetic stirring apparatus 6, concentrated hydrochloric acid is slowly added drop-wise to by constant pressure funnel 7 in the there-necked flask 1 that the vitriol oil is housed produces dry hydrogen chloride gas, adjusting gas flow voluntarily, now-making-now-using, dry hydrogen chloride gas (20 L ± 5 L) is slowly passed into in there-necked flask 3 by closed tube 2 and gas meter, reflux, phenylhydrazine (the 54.6g of 88.6g is slowly dripped again by constant pressure funnel 9, 99%) with the mixing solutions of methyl alcohol (32g) in there-necked flask 3, about 0.5 ~ 1h dropwises, continue backflow 1h, after reaction terminates, hot solution is poured in the beaker of 500mL, after vigorous stirring, product is slowly separated out from methanol solution, add the distilled water of 250mL, product is then separated out in a large number, leave standstill and filter, with distilled water wash three times to neutral, obtain white crystal, dry to obtain the tetrahydro carbazole of 84.8g, yield 99.1%, HPLC content is 99.3%.
Embodiment 2
Put up experimental installation by shown in Fig. 1, in there-necked flask 3, add 54g(0.55mol by constant pressure funnel 9) pimelinketone, 138g(3mol) ethanol, be uniformly mixed by magnetic stirring apparatus 6, concentrated hydrochloric acid is slowly added drop-wise to by constant pressure funnel 7 in the there-necked flask 1 that the vitriol oil is housed produces dry hydrogen chloride gas, adjusting gas flow voluntarily, now-making-now-using, dry hydrogen chloride gas (20 L ± 5 L) is slowly passed into in there-necked flask 3 by closed tube 2 and gas meter, reflux, phenylhydrazine (the 54.6g of 100.6g is slowly dripped again by constant pressure funnel 9, 99%) with the mixing solutions of ethanol (46g) in there-necked flask 3, about 0.5 ~ 1h dropwises, continue backflow 1h, after reaction terminates, hot solution is poured in the beaker of 500mL, vigorous stirring, product is slowly separated out from ethanolic soln, add the water of 250mL, product then settles out in a large number, leave standstill and filter, wash and obtain white crystal to neutrality three times, dry to obtain the tetrahydro carbazole of 83.9g, yield 98.1%, HPLC content is 98.7%.
Embodiment 3
Experimental installation is put up by shown in Fig. 1, in there-necked flask 3, add 54g(0.55mol by constant pressure funnel 9) pimelinketone, 110g(methyl alcohol: the amount of substance of ethanol is than being 2:1) methyl alcohol and the mixing solutions of ethanol, be uniformly mixed by magnetic stirring apparatus 6, concentrated hydrochloric acid is slowly added drop-wise to by constant pressure funnel 7 in the there-necked flask 1 that the vitriol oil is housed produces dry hydrogen chloride gas, adjusting gas flow voluntarily, now-making-now-using, dry hydrogen chloride gas (20 L ± 5 L) is slowly passed into in there-necked flask 3 by closed tube 2 and gas meter, reflux, phenylhydrazine (the 54.6g of 100.6g is slowly dripped again by constant pressure funnel 9, 99%) with the mixing solutions of methyl alcohol (32g) in there-necked flask 3, about 0.5 ~ 1h dropwises, continue backflow 1h, after reaction terminates, hot solution is poured in the beaker of 500mL, vigorous stirring, product is slowly separated out from the mixing solutions of methanol/ethanol, the aquatic products thing adding 250mL settles out in a large number, leave standstill and filter, wash and obtain white crystal to neutrality three times, dry to obtain the tetrahydro carbazole of 84.5g, yield 98.8%, HPLC content is 98.9%.
Embodiment 4
Experimental installation is put up by shown in Fig. 1, in there-necked flask 3, add 54g(0.55mol by constant pressure funnel 9) pimelinketone, 110g(methyl alcohol: the amount of substance of ethanol is than being 2:1) methyl alcohol and the mixing solutions of ethanol, be uniformly mixed by magnetic stirring apparatus 6, concentrated hydrochloric acid is slowly added drop-wise to by constant pressure funnel 7 in the there-necked flask 1 that the vitriol oil is housed produces dry hydrogen chloride gas, adjusting gas flow voluntarily, now-making-now-using, dry hydrogen chloride gas (20 L ± 5 L) is slowly passed into in there-necked flask 3 by closed tube 2 and gas meter, reflux, phenylhydrazine (the 54.6g of 100.6g is slowly dripped again by constant pressure funnel 9, 99%) with the mixing solutions of ethanol (46g) in there-necked flask 3, about 0.5 ~ 1h dropwises, continue backflow 1h, after reaction terminates, hot solution is poured in the beaker of 500mL, vigorous stirring, product is slowly separated out from methanol/ethanol mixing solutions, the aquatic products thing adding 250mL settles out in a large number, leave standstill and filter, wash and obtain white crystal to neutrality three times, dry to obtain the tetrahydro carbazole of 84.0g, yield 98.2%, HPLC content is 99.2%.
Claims (2)
1. the preparation method of a tetrahydro carbazole, it is characterized in that: pimelinketone and methanol/ethanol or the mixing solutions of the two are mixed, reflux, passes into dry HCl gas as catalyzer, slowly add phenylhydrazine and methanol/ethanol or the mixing solutions of the two again, continue backflow; After reaction terminates, cooling reaction solution, namely product slowly separates out with crystallite form from methanol/ethanol or the two mixing solutions, adding with the mass ratio of methanol/ethanol or the two mixing solutions is again the distilled water of 1:0.8 ~ 1:1.5, further precipitation product, filter and distilled water wash extremely neutrality, drying can obtain the tetrahydro carbazole product of purity > 98.6%; The mass ratio of described phenylhydrazine and methanol/ethanol or the mixing solutions of the two is 1:5 ~ 10; Described phenylhydrazine and the mass ratio of pimelinketone are 1:1.1 ~ 1.5; The purity of described phenylhydrazine is between 95% ~ 99.5%.
2. the preparation method of tetrahydro carbazole as claimed in claim 1, is characterized in that: the mass ratio of phenylhydrazine and methanol/ethanol or the mixing solutions of the two is 1:6 ~ 8; Described phenylhydrazine and the mass ratio of pimelinketone are 1:1.2 ~ 1.4; The purity of described phenylhydrazine is 99%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1962635A (en) * | 2006-11-17 | 2007-05-16 | 浙江工业大学 | Indoles compound preparation method |
| CN101508669A (en) * | 2009-03-26 | 2009-08-19 | 浙江工业大学 | Green synthesis of indole compounds |
| CN102249983A (en) * | 2011-05-24 | 2011-11-23 | 南通海迪化工有限公司 | Method for synthesizing tetrahydrocarbazoles compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1962635A (en) * | 2006-11-17 | 2007-05-16 | 浙江工业大学 | Indoles compound preparation method |
| CN101508669A (en) * | 2009-03-26 | 2009-08-19 | 浙江工业大学 | Green synthesis of indole compounds |
| CN102249983A (en) * | 2011-05-24 | 2011-11-23 | 南通海迪化工有限公司 | Method for synthesizing tetrahydrocarbazoles compound |
Non-Patent Citations (2)
| Title |
|---|
| One-Step Synthesis of 1,2,3,4-Tetrahydrocarbazole and 1,2-Benzo-3,4-dihydrocarbazole;Crosby U.Rogers，B.B.Corson;《J.Am.Chem.Soc.》;19471231;第69卷(第11期);第2910页实验部分第3段 * |
| 咔唑合成方法的研究;俞马金 等;《染料工业》;19981231;第35卷(第3期);第22页2.成环反应 * |
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