KR100766615B1 - Process for preparing 4-hydroxycarbazole - Google Patents

Abstract

The present invention relates to a method for preparing 4-hydroxy carbazole, and more particularly, after obtaining 2-chlorocyclohexanone through selective monochlorination of cyclohexanone, 1, Cyclocyclization with 3-cyclohexanedione to give 3,4,5,7,8,9-hexahydro-2H-dibenzofuran-1-one, wherein 3,4,5,7,8,9 Oxygen of -hexahydro-2H-dibenzofuran-1-one was replaced with nitrogen to obtain 1,2,3,5,6,7,8,9-octahydrocarbazol-4-one, which was then palladium Dehydrogenation in the presence of a catalyst relates to a process for preparing 4-hydroxycarbazole. According to the method of the present invention, by using a low-cost cyclohexanone as a starting material to improve the economics of the process, the 4-hydroxycarbazole, a tricyclic compound in a very simple, efficient and environmentally friendly method than the conventional manufacturing method It can manufacture.

4-hydroxycarbazole, hexahydro-2H-dibenzofuran-1-one, octahydrocarbazole-4-one, selective monochloride reaction, cyclization reaction, nitrogen substitution reaction, dehydrogenation reaction

Description

Process for preparing 4-hydroxycarbazole

The present invention relates to a method for preparing 4-hydroxycarbazole, and more particularly, 4-, through a monochlorination reaction, a cyclization reaction, a nitrogen substitution reaction, and a dehydrogenation reaction using cyclohexanone as a starting material. It relates to a method for efficiently preparing hydroxycarbazole.

4-hydroxycarbazole is Roche's non-selective beta inhibitor and is an intermediate of carvedilol, a therapeutic agent for hypertension. 4-hydroxycarbazole is used not only for carvedilol but also as an important precursor for other pharmaceuticals.

As a method for synthesizing such 4-hydroxycarbazole, a method using bromonitrobenzene and iodoanisol disclosed in Boehringer Mannheim's 1974 German Patent No. 2240599 and a method using chloronitrobenzene and dinitrobiphenyl There is this. However, in this patent, there is a problem to use industrially by using very economical and dangerous hydrazoic acid (HN ₃ ) as a starting material.

Meanwhile, US Patent No. 4,273,711 in 1981 discloses cyclohexane-1,3-ion-monophenyl hydrazone obtained by reacting cyclohexanedione with phenylhydrazine by Fischer rearrangement using zinc chloride. A process for producing 4-hydroxycarbazole is disclosed, after obtaining 2,3,4, -tetrahydro-4-oxo-carbazole, followed by dehydrogenation under a nickel catalyst. However, the production method uses acetic acid that causes an irritating odor during production, not only the reaction yield is not good, but also the reaction time is too long in the dehydration reaction, there is an uneconomical problem in industrial production.

Therefore, in the present invention, as a result of repeated research on a new method of synthesizing a tricyclic aromatic compound in order to solve the above-mentioned problems of the prior art, it is possible to achieve cost improvement by using a cheaper starting material, and to be environmentally friendly, which is not irritating or dangerous. Using the phosphorus raw material, 4-hydroxycarbazole could be efficiently produced, and the present invention was completed based on this.

Accordingly, it is an object of the present invention to provide a method for economically manufacturing 4-hydroxycarbazole through a process which is economical and uses an inexpensive starting material and is more efficient and environmentally friendly than a conventional manufacturing method.

Method for producing 4-hydroxycarbazole represented by the following formula (1) of the present invention for achieving the above object is to a) mono-chlorinated cyclohexanone using sulfonyl chloride in the presence of a solvent and a drying agent Obtaining 2-chlorocyclohexanone represented by Formula 2; b) 3,4,5,7,8,9-hexa represented by the following Chemical Formula 3 by cyclization reaction of 2-chlorocyclohexanone and 1,3-cyclohexanedione represented by Chemical Formula 2 under basic conditions Obtaining hydro-2H-dibenzofuran-1-one; c) Substituting and reacting 3,4,5,7,8,9-hexahydro-2H-dibenzofuran-1-one represented by Chemical Formula 3 with nitrogen using ammonia or ammonia water to replace oxygen in the molecule Obtaining 1,2,3,5,6,7,8,9-octahydrocarbazol-4-one represented by 4; And d) dehydrogenating 1,2,3,5,6,7,8,9-octahydrocarbazol-4-one represented by Formula 4 in the presence of a high boiling point solvent and a metal catalyst; Include.

Looking at the present invention in more detail as follows.

As described above, in the present invention, 4-hydroxycarbazole is economically and environmentally prepared through monochlorination, cyclization, nitrogen substitution, and dehydrogenation using cyclohexanone as a low-cost starting material. A method is provided.

According to the present invention, first, a monochloride reaction of cyclohexanone, which is a starting material, using sulfonyl chloride in the presence of a solvent and a drying agent is selectively carried out to obtain 2-chlorocyclohexanone represented by Chemical Formula 2. Through the monochloride reaction, 2-chlorocyclohexanone is optionally substituted with one chlorine at the alpha position of cyclohexanone.

The solvent used in the monochloride reaction is normal hexane, normal heptane, benzene, toluene, xylene, diethyl ether, dinormal butyl ether, methyl neobutyl ether, isopropyl ether, tetrahydrofuran, dichloromethane, chloroform, dichloroethane , Methanol, ethanol, butanol, isobutyl alcohol, isopropyl alcohol, acetonitrile, dimethylformamide and the like, and at least one selected from the group consisting of benzene, toluene, xylene, tetrahydrofuran, acetonitrile and dichloro One or more selected from methane, chloroform and the like can be used, and most preferably, benzene, toluene, xylene, or a mixture thereof is used.

In addition, the desiccant used in the monochloride reaction includes magnesium sulfate, anhydrous sodium sulfate, calcium chloride, molecular sieve of 4 Å, calcium sulfate, and the like, preferably anhydrous sodium sulfate or magnesium sulfate. . When such a desiccant is not used, the selectivity decreases because the byproducts of cyclohexanone in which 2 to 4 chlorine are substituted at the alpha position of cyclohexanone produced are increased.

On the other hand, since the monochloride reaction is exothermic, it is preferable to maintain a reaction temperature of 0 to 25 ° C. when sulfonyl chloride is added. In addition, the equivalent ratio of the sulfonyl chloride added is preferably 1.0 to 2.0 with respect to the cyclohexanone. When the equivalent ratio is less than 1.0, the reaction conversion rate decreases. When the equivalent ratio exceeds 2.0, the byproducts increase to decrease the selectivity.

When the dropwise addition of the sulfonyl chloride is completed, the temperature is gradually decreased to room temperature. At this time, the reaction temperature of the monochlorination reaction is 5 to 25 ℃, the reaction time is preferably 1 to 3 hours, the reaction temperature is high or the reaction time is long, so the selectivity of the reaction is not good.

Then, the 2-chlorocyclohexanone represented by Formula 2 obtained therefrom is cyclized with 1,3-cyclohexanedione under basic conditions to give 3,4,5,7,8 represented by Formula 3 , 9-hexahydro-2H-dibenzofuran-1-one is obtained.                     

Bases used for the cyclization reaction include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, calcium hydroxide, magnesium hydroxide, lithium hydroxide, and the like, preferably potassium carbonate, potassium hydroxide, sodium hydroxide, Or mixtures thereof.

On the other hand, the cyclization reaction is preferably carried out for 3 to 20 hours at a temperature of 0 ~ 150 ℃, preferably 60 ~ 80 ℃, if the reaction temperature is low, it takes a lot of reaction time is not economical.

After the cyclization reaction is completed, the temperature of the reactant is lowered to 10 ° C. or lower, and slowly added to 0˜10 ° C. water, followed by filtration to be represented by Chemical Formula 3 without undergoing a separate recrystallization or purification process. 3,4,5,7,8,9-hexahydro-2H-dibenzofuran-1-one can be obtained economically.

Thereafter, 3,4,5,7,8,9-hexahydro-2H-dibenzofuran-1-one represented by Chemical Formula 3 obtained therefrom is reacted with an equivalent or more of ammonia or aqueous ammonia to give 3,4, 1,2,3,5,6,7,8,9-octa represented by the formula (4) by replacing oxygen of 5,7,8,9-hexahydro-2H-dibenzofuran-1-one with nitrogen Hydrocarbazol-4-one is obtained.

In this case, when the ammonia is used as a reactant, it is advantageous to use a solvent capable of dissolving the reactant and the product, and available solvents include normal hexane, normal heptane, benzene, toluene, xylene, diethyl ether, and dinormal At least one selected from the group consisting of butyl ether, methyl neobutyl ether, isopropyl ether, tetrahydrofuran, 1,4-dioxane, diglyme, methanol, ethanol, butanol, isobutyl alcohol, isopropyl alcohol, and the like Can be. In addition, the equivalent ratio of the ammonia is preferably 2 to 30 relative to the 3,4,5,7,8,9-hexahydro-2H-dibenzofuran-1-one, and the reaction conversion ratio is less than 2 when the equivalent ratio is less than 2. Decrease, above 30 is not economical. On the other hand, the substitution reaction is preferably carried out for 2 to 60 hours at a reaction temperature of 50 to 250 ℃, it is uneconomical if the reaction temperature and the reaction time is out of the range.

After the substitution reaction is completed, the temperature of the reactant is lowered to 25 ° C. or lower to precipitate the reaction product in a solid state, and 1,2,3,5,6,7,8 represented by Chemical Formula 4 without undergoing a separate purification step. , 9-octahydrocarbazol-4-one can be obtained.

Thereafter, 1,2,3,5,6,7,8,9-octahydrocarbazol-4-one represented by Chemical Formula 4 is subjected to dehydrogenation reaction in the presence of a high boiling point solvent and a metal catalyst. 4-hydroxycarbazole represented by is obtained.

As the solvent used for the dehydrogenation reaction, one or more selected from the group consisting of cumene, trimethylbenzene, trichlorobenzene, methylnaphthalene, dimethylnaphthalene, diglyme, triglyme, and the like may be used. It is preferable to use a solvent having a boiling point of 180 ° C. or higher, such as benzene, methylnaphthalene, dimethylnaphthalene, and triglyme.

In addition, as the metal catalyst used in the dehydrogenation reaction, one of palladium-carbon, palladium-alumina, and palladium-calcium carbonate may be selected. On the other hand, the dehydrogenation reaction is preferably carried out for 2 to 60 hours at a reaction temperature of 140 ~ 350 ℃, if the reaction temperature is less than 140 ℃ is less reactivity, if it exceeds 350 ℃ selectivity falls. In addition, when the reaction time is out of the range, the selectivity is lowered and it is not economical.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited thereto.

Example 1

(1) Preparation of 2-chlorocyclohexanone

Cyclohexanone (100 g) and magnesium sulfate (50 g) were put in a 2 L reaction vessel, and then 1 L of toluene was added and stirred. Sulfonyl chloride (SO ₂ Cl ₂ ) (165g) is slowly added thereto. Since the heat is generated when the sulfonyl chloride is added dropwise to adjust the temperature of the reaction solution to less than 10 ℃ to prevent the temperature rise.

When the dropwise addition of sulfonyl chloride is completed, the temperature is gradually decreased to room temperature and stirred for 2 hours. After the reaction, magnesium sulfate was filtered and 1L of water was added to remove the remaining sulfonyl chloride. At this time, toluene was added to the aqueous layer and extracted twice or more, and the aqueous layer was removed. The solvent was distilled off under reduced pressure to give 2-chlorocyclohexanone (127.6 g).

(2) Preparation of 3,4,5,7,8,9-hexahydro-2H-dibenzofuran-1-one

1,3-cyclohexanedione (93.02 g) is added to a 1 L reactor. Put a base solution of sodium hydroxide (39.22g) in water (200ml) and stir. At this time, since there is exotherm, while stirring the solution (methanol (200ml) is added while stirring so that the temperature of the solution does not become more than 25 ℃. Here, 2-chlorocyclohexanone (100 g) obtained in the above (1) was slowly added and stirred. After slowly raising the temperature of the reaction to 60 ° C. and confirming that the reaction proceeds after 10 hours, when the temperature of the reaction solution is lowered to 5 ° C., 3,4,5,7,8,9-hexahydro-2H-dibenzofuran- 1-one precipitates in solid state. This was slowly added to 800 ml of water at 10 ° C., and then filtered to obtain 98% pure 3,4,5,7,8,9-hexahydro-2H-dibenzofuran-1-one without additional recrystallization or purification. (100.43 g) was obtained.

(3) Preparation of 1,2,3,5,6,7,8,9-octahydrocarbazol-4-one

3,4,5,7,8,9-hexahydro-2H-dibenzofuran-1-one (100 g) and ammonia water (600 g, Assay 25% as NH ₃ ) obtained in the above (2) were added to a batch high pressure reactor. And replace the air in the reactor with nitrogen. When the internal air is completely replaced with nitrogen, the temperature of the reactor is raised to 130 ° C. while strongly stirring the reactor. After confirming that the reaction proceeds after 20 hours, when the reactor temperature is lowered to room temperature, 1,2,3,5,6,7,8,9-octahydrocarbazol-4-one precipitates in a solid state. This was filtered to give 1,2,3,5,6,7,8,9-octahydrocarbazol-4-one (84.1 g) with 98% purity.

(4) Preparation of 4-hydroxycarbazole

1,2,3,5,6,7,8,9-octahydrocarbazol-4-one (50 g) and trichlorobenzene (bp = 230-270 C, 300 g) obtained in the above (3), and 5% Pd / C catalyst (5 g) is added to a batch reactor. At this time, in order to remove hydrogen generated during the reaction and to block the inflow of external air in the reactor, the reactor internal temperature is raised to 230 ° C. while flowing nitrogen into the reactor. Continue to stir the reactor and pour nitrogen while the reaction proceeds, until the conversion of 1,2,3,5,6,7,8,9-octahydrocarbazol-4-one reaches 99% or more To last.

After the reaction is completed, the reaction solution is filtered at high temperature to remove the catalyst. When the temperature of the reaction filtrate is gradually lowered to room temperature, 4-hydroxycarbazole is formed and precipitates in a solid state. This was filtered, dissolved in 300ml of toluene at high temperature, and n-hexane (600ml) was slowly added to precipitate crystals. After dropping the solution temperature to room temperature, the resulting solid was filtered to obtain 4-hydroxycarbazole (34 g) with 98% purity.

Example 2

98% by the same method as in Example 1, except that 5% of Pd / Al ₂ O ₃ catalyst was used instead of 5% of Pd / C catalyst to prepare 4-hydroxycarbazole in (4). Purity 4-hydroxycarbazole (36.4 g) was obtained.

As described above, according to the present invention, 4-hydroxycarbazole, which is a tricyclic aromatic compound, can be efficiently produced using a low-cost starting material, cyclohexanone, through an economical and unique process compared to the conventional method. . In addition, the process according to the invention is environmentally friendly with the use of non-hazardous raw materials and advantageous for industrial use.

Claims (10)

a) selectively monochlorinating cyclohexanone using sulfonyl chloride in the presence of a solvent and a drying agent to obtain 2-chlorocyclohexanone represented by the following formula (2); b) 3,4,5,7,8,9-hexa represented by the following Chemical Formula 3 by cyclization reaction of 2-chlorocyclohexanone and 1,3-cyclohexanedione represented by Chemical Formula 2 under basic conditions Obtaining hydro-2H-dibenzofuran-1-one; c) Substituting and reacting 3,4,5,7,8,9-hexahydro-2H-dibenzofuran-1-one represented by Chemical Formula 3 with nitrogen using ammonia or ammonia water to replace oxygen in the molecule Obtaining 1,2,3,5,6,7,8,9-octahydrocarbazol-4-one represented by 4; And d) dehydrogenating 1,2,3,5,6,7,8,9-octahydrocarbazol-4-one represented by Formula 4 in the presence of a high boiling point solvent and a metal catalyst; Wherein the drying agent of step a) is selected from the group consisting of magnesium sulfate, anhydrous sodium sulfate, potassium chloride, a molecular sieve of 4 ′, and calcium sulfate, and the high boiling point solvent of step d) is cumene, Trimethylbenzene, trichlorobenzene, methylnaphthalene, diglyme, triglyme, and mixtures thereof, wherein the metal catalyst of step d) is palladium-carbon, palladium-alumina, or palladium-calcium carbonate Method for preparing 4-hydroxycarbazole represented by the following Chemical Formula 1, characterized in that: Formula 1

Formula 2

Formula 3

Formula 4

. delete The method of claim 1, wherein the solvent of step a) is normal hexane, normal heptane, benzene, toluene, xylene, diethyl ether, dinormal butyl ether, methyl neobutyl ether, isopropyl ether, tetrahydrofuran, dichloromethane, Chloroform, dichloroethane, methanol, ethanol, butanol, isobutyl alcohol, isopropyl alcohol, acetonitrile, dimethylformamide, and mixtures thereof. According to claim 1, wherein the base in step b) is used with a base solution selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, calcium hydroxide, magnesium hydroxide, lithium hydroxide, and mixtures thereof Characterized in that the method. delete delete The method of claim 1, wherein the equivalent ratio of sulfonylchloride to cyclohexanone of step a) is 1.0 to 2.0. The method of claim 1, wherein the equivalent ratio of ammonia to 3,4,5,7,8,9-hexahydro-2H-dibenzofuran-1-one of step c) is 2 to 30. . According to claim 1, wherein the monochloride reaction of step a) is carried out for 1 to 3 hours at a temperature of 5 to 25 ℃, the cyclization reaction of step b) is 3 to 20 hours at a temperature of 0 to 150 ℃ Characterized in that during the process. According to claim 1, wherein the substitution reaction of step c) is carried out for 2 to 60 hours at a temperature of 50 to 250 ℃, the dehydrogenation of step b) is carried out for 2 to 60 hours at a temperature of 40 to 350 ℃ Characterized in that it is carried out.