KR20030008948A - Process for the preparation of ondansetron and pharmaceutically acceptable salts thereof - Google Patents

Abstract

PURPOSE: A method for producing ondansetron and salts thereof is provided, thereby simply and cheaply producing the high purity ondansetron. CONSTITUTION: The method for producing 1,2,3,9-tetrahydro-9-methyl-3-((2 - methyl-1H-imidazole-1-il) methyl)-4H-carbazol-4-on (ondansetron) represented by formula(1) and salts thereof is characterized by the reaction of 1-(substituted methyl)-2-methylimidazole derivative represented by formula(2) with 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-on represented by formula(3) in the presence of an acid catalyst, wherein R1 is R2R3N-, 1-morpholinyl or halogen; R2 and R3 are independently C1-C5 lower alkyl, benzyl or alkoxy, or R2 and R3 are C1-C5 cyclic alkyl together; the acid catalyst is hydrochloric acid, methane sulfonic acid, formic acid, trifluoro acetic acid, chloro sulfonic acid, sulfuric acid or hexane.

Description

PROCESS FOR THE PREPARATION OF ONDANSETRON AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

The present invention relates to 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] of formula (1) which is a selective 5-HT ₃ receptor antagonist -4H-carbazol-4-one (ondansetron) and its pharmaceutically acceptable acid addition salts.

Ondansetron is a compound introduced for the first time in European Patent No. 191,562. It has a high selectivity and acts on 5-HT ₃ receptors to show anti-anxiety, anti-affective action, etc. It is widely used to prevent and treat vomiting.

Korean Patent Publication No. 92-3064 (priority British Patent Application 84-01888), as shown in Scheme 1 below,

(Scheme 1)

A method for synthesizing ondansetron is described by heating a 3-substituted carbazolone derivative of formula (4) and 2-methylimidazole of formula (5) in an appropriate solvent. Wherein Y is a reactive substituent.

The compound of formula (4) is a compound obtained by reacting 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of formula (3) with formaldehyde and dialkylamine. It includes a compound of formula (6) and formula (7).

However, the patent specification of this method does not describe the preparation method of compound (6), and in fact, the inventors have found that the compound (6) has been produced through a very difficult process and has a low yield. Another compound (7) is also described as being obtained from the compound (6) by treating the intermediate obtained by reflux heating with highly methane iodide with reflux for 57 hours.

This method requires the synthesis of the intermediate used in the manufacturing process and the synthesis of the final ondansetron require a long time reaction under high temperature, and the yield is also very low.

Korean Patent Publication No. 92-1670 discloses an intermediate compound of formula (10) by the reaction of phenylhydrazine of formula (8) with a substituted cyclohexadione derivative of formula (9), as shown in Scheme 2 below. Next, a method for synthesizing ondansetron is described.

(Scheme 2)

This method involves a reaction pathway similar to the Fischer indole synthesis method, in which the entire process takes several steps, both the carbazolone ring formation and the previous hydrazone synthesis process require vigorous reaction conditions as well as overall yield. (9% of the total) is also very low.

In addition, Korean Patent Publication No. 92-1671 discloses an enol ether of formula (11) from imidazolylmethyl-1,3-cyclohexanedione and reacts with 2-iodoaniline, as shown in Scheme 3 below. To synthesize an intermediate (12), which is then subjected to a ring formation reaction with a catalyst to synthesize an intermediate (13), and then a reaction to introduce a methyl group to synthesize ondansetron is described. .

(Scheme 3)

Disadvantages of this process are the long manufacturing process starting from the preparation of imidazolylmethyl-1,3-cyclohexanedione of formula (9), and the overall yield including cyclization reaction is very low ( Total yield: 4%). Another disadvantage of this method is that expensive noble metals should be used as catalysts in the cyclization reaction, which leads to a low yield and greatly impedes the economics of the manufacturing process itself.

Korean Patent Application No. 93-3609 (Publication No. 93-19665) describes a method for preparing ondansetron by ring forming reaction from Compound (14), as shown in Scheme 4 below.

(Scheme 4)

If ondansetron is to be prepared by this method, compound (15) must be synthesized from compound (14), which is not a commercially available material. Therefore, to prepare ondansetron by this method, it has to go through a very long multi-step reaction process, and the overall yield including ring formation reaction with low yield is too low to secure economic feasibility.

On the other hand, Korean Patent Publication Nos. 98-32228 and 98-32229 disclose 1,2,3,9-tetrahydro-9-methyl-3-methylene- of Formula (16), as shown in Scheme 5 below. A process for preparing ondansetron of formula (1) is described by synthesizing 4H-carbazol-4-one and then reacting it with 2-methylimidazole in the presence of Lewis acid.

(Scheme 5)

In order to prepare ondansetron according to this method, in order to prepare an intermediate compound of formula (16), acetic acid, which is difficult to use after use, is used as a reaction solvent, and then heated to reflux for a long time, and then acetic acid is removed by distillation. However, due to the poor color and purity of the reaction intermediates and the final product, a complex purification process is required. As a result, the overall yield is lowered and the economical efficiency is lowered along with the treatment of the waste liquid.

Accordingly, it is an object of the present invention to provide a novel process which can produce ondansetron and its pharmaceutically acceptable acid addition salts economically as well as high purity under industrially simple and mild reaction conditions.

According to the above object, in the present invention, a new synthesis of 1- (substituted methyl) -2-methylimidazole compound of formula (2) obtained by reacting 2-methylimidazole with secondary amine and formaldehyde, 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H) of formula (1), characterized by reacting carbazolone of formula (3) in the presence of an acid catalyst as shown in Scheme 6. -Imidazol-1-yl) methyl] -4H-carbazol-4-one (ondansetron) and pharmaceutically acceptable salts thereof are provided.

(Scheme 6)

Wherein R ¹ is R ² R ³ N-, 1-morpholinyl, or halogen, and R ² and R ³ are each C ₁ -C ₅ lower alkyl, benzyl, alkoxy, or the like, or R ² and R ³ together represents a cyclic alkyl C ₁ -C _5.

Representative R ¹ in the present invention is a symmetric secondary amino group such as N, N-dimethylamino, N, N-diethylamino, morpholin-4-yl, piperidin-1-yl or N, O-dimethylhydroxyl Asymmetric secondary amino groups, such as amino and N, N-benzylmethylamino.

1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of formula (3) used as starting material in the process of the present invention is a known compound and is a commercially available compound. . The 1-substituted methyl-2-methylimidazole derivatives of formula (2) are known compounds described in Tetrahedron Letters, 1990, 31 (40), 5779 and Journal of Organic Chemistry, 1988, 53, 5685. Or can be readily prepared and used in high yields by the methods described in the literature.

In the above Scheme 6, the compound of formula (2) is preferably used in the amount of 1 to 10 equivalents, and most preferably 1 to 2 equivalents based on the compound of formula (3) which is another reactant.

The reaction includes halogenated hydrocarbons such as methylene chloride and chloroform, acetonitrile, ethers such as tetrahydrofuran and 1,4-dioxane, aromatics such as toluene and benzene, and N, N-dimethylformamide, or N, Amides such as N-dimethylacetamide, or a mixture of two or more thereof can be used as the reaction solvent.

The reaction is preferably carried out in the presence of a suitable acid catalyst, wherein the acid catalysts advantageous for use are hydrochloric acid, methanesulfonic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, chlorosulfonic acid, sulfuric acid, or hexanoic acid. Acids, such as these, can be used. It is also possible to use Lewis acids in addition to the usual hydrogen acids. Examples of the Lewis acid catalyst that can be used include metal halides such as aluminum chloride, zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, ferric chloride, titanium chloride, and aluminum oxide. The amount of the acid catalyst to be used at this time is preferably 0.1 to 5 equivalents, most preferably 0.8 to 2.2 equivalents based on the compound of formula (3).

The reaction can be carried out usually in the range of room temperature to 150 ° C, preferably at room temperature to 100 ° C. The reaction time is preferably carried out for 2 hours to 24 hours, preferably 2 hours to 12 hours.

When the reaction is complete, water can be added to the reaction system and stirred to terminate the reaction and the product can be separated. The product may be separated from the reaction solution in the form of a salt, or may be extracted and separated without being a salt. The ondansetron thus obtained may be further purified through a conventional purification process, or may be used to prepare a pharmaceutically useful acid addition salt according to conventional methods in the art.

The compound of formula (1) may be prepared directly from the reaction solution by the process of the present invention, or may be prepared in a non-salt state and then made into a useful salt form. For example, for the preparation of pharmaceutically useful hydrochloride dihydrate, the product obtained by the process can be prepared by purification if necessary, then dissolved in an appropriate proportion of hydrochloric acid and crystallized from this hydrochloric acid solution.

Compared with the existing methods, the present invention has the advantage that the compound of formula (2) can be used to produce the target compound in high yield and high purity by economically short reaction route.

In order to demonstrate the usefulness of the present invention will be described in detail by the following examples, but the technical spirit and scope of the present invention is not limited thereto.

(Example 1)

1- (N, N-dimethylaminomethyl) -2-methylimidazole

10 g of 2-methylimidazole and 10 g of dimethylamine hydrochloride were dissolved in 25 ml of distilled water, and concentrated hydrochloric acid was added so that the solution had a pH of 5. 11 ml of an aqueous 36% formaldehyde solution was added and reacted at room temperature for 24 hours. The reaction was adjusted to alkaline using 20% potassium hydroxide solution, saturated with potassium carbonate and extracted with dichloromethane. The organic layer was dried over anhydrous potassium carbonate, the solvent was removed under reduced pressure, and the residue was distilled under reduced pressure to obtain 13.9 g (82%) of 1- (N, N-dimethylaminomethyl) -2-methylimidazole as a target compound. Got it.

¹ H-NMR (CDCl3) (ppm): 2.27 (s, 6H), 2.41 (s, 3H), 4.45 (s, 2H), 6.87 (d, 2H)

(Example 2)

1- (N, N-diethylaminomethyl) -2-methylimidazole

10 g of 2-methylimidazole and 13.4 g of diethylamine hydrochloride were dissolved in 25 ml of distilled water, and the pH of the reaction solution was adjusted to 5 using concentrated hydrochloric acid. 11 ml of an aqueous 36% formaldehyde solution was added and reacted at room temperature for 24 hours. The solution was adjusted to alkaline using 20% potassium hydroxide solution, the reaction was saturated with potassium carbonate and then extracted with dichloromethane. The organic layer was dried over anhydrous potassium carbonate, the solvent was removed under reduced pressure, and the residue was distilled under reduced pressure to give 16.3 g (80%) of 1- (N, N-diethylaminomethyl) -2-methylimidazole as a target compound. Got.

¹ H-NMR (CDCl 3) (ppm): 1.11 (t, 6H), 2.40 (s. 3H), 2.59 (q, 4H), 4.42 (s, 2H),

6.86 (d, 2H)

(Example 3)

1- (N, O-dimethylhydroxyamino) -2-methylimidazole

10 g of 2-methylimidazole and 11.88 g of N, O-dimethylhydroxylamine hydrochloride were dissolved in 25 ml of distilled water, and the pH was adjusted to 5 with concentrated hydrochloric acid. 11 g of an aqueous 36% formaldehyde solution was added thereto and reacted at room temperature for 24 hours. The solution was made alkaline with 20% potassium hydroxide solution, then saturated with potassium carbonate and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous potassium carbonate, and the solvent was evaporated under reduced pressure to obtain 13.2 g (70%) of 1- (N, O-dimethylhydroxyamino) -2-methylimidazole as a target compound.

¹ H-NMR (CDCl3) δ: 2.39 (s, 3H), 2.57 (s, 3H), 3.26 (s, 3H), 4.57 (s, 2H), 6.87 (d, 1H), 6.93 (d, 2H)

(Example 4)

1- (N, N-benzylmethylamino) -2-methylimidazole

10 g of 2-methylimidazole and 14.76 g of N-benzylmethylamine were dissolved in 25 ml of distilled water, and the pH was adjusted to 5 with concentrated hydrochloric acid. 11 g of an aqueous 36% formaldehyde solution was added thereto and reacted at room temperature for 24 hours. The solution was made alkaline with 20% potassium hydroxide solution, then saturated with potassium carbonate and extracted with ethyl acetate. The organic layer was washed twice with water, dried over potassium carbonate, and the solvent was distilled off under reduced pressure to obtain 17.1 g (65%) of 1- (N, N-benzylmethylamino) -2-methylimidazole as a target compound.

¹ H-NMR (CDCl3) (ppm): 2.23 (s, 3H), 2.34 (s, 3H), 3.63 (s, 2H), 4.57 (s, 2H), 6.91 (d, 2H), 7.32 (m, 5H)

(Example 5)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate

16.70 g of 1- (N, N-dimethylaminomethyl) -2-methylimidazole and 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one prepared in Preparation Example 1 19.93 g were dissolved in 200 ml of acetonitrile. 30 ml of concentrated hydrochloric acid was added to the mixture, and the reaction was allowed to react for 8 hours while heating to reflux. The reaction was cooled to 0 ° C. and stirring continued slowly for 5 hours at the same temperature to crystallize the product. The resulting crystals were filtered to afford 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4 as the target compound. 29.3 g (80%) of-warm hydrochloride dihydrate was obtained.

Melting Point (℃): 178.5-179.5

¹ H-NMR (DMSO-d ₆₎ (ppm): (1.88 to 2.06 (m, 1H), 2.10 to 2.23 (m.1H), 2.65 (s, 3H),

2.95 to 3.23 (m, 3H), 3.74 (s, 3H), 4.27 (dd, 1H), (dd, 1H), 7.20 (m, 2H), 7.56 (m, 2H), 8.00 (d, 1H))

Water (Karlfisher): 9.95% (Theoretical: 9.85%)

(Example 6)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate

16.70 g of 1- (N, N-dimethylaminomethyl) -2-methylimidazole and 19.93 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one were added to dimethylformamide. After addition to 200 ml, 30 ml of concentrated hydrochloric acid was added. The reaction was heated at 80 ° C. for 8 hours and the reaction was complete and then cooled to 5 ° C. 200 ml of tetrahydrofuran was added to the reaction mixture to crystallize. The resulting crystals were filtered to afford 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4 as the target compound. 27.4 g (75%) of warm, hydrochloride and dihydrate were obtained. The obtained product was analyzed to be the same material as obtained in Example 5.

(Example 7)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate

Aceto 20.2g of 1- (N, O-dimethylhydroxyaminomethyl) -2-methylimidazole and 19.93g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one After addition to 200 ml of nitrile, 20 ml of concentrated hydrochloric acid was added. The reaction was heated at 80 ° C. for 8 hours and the reaction was complete and then cooled to 5 ° C. 200 ml of tetrahydrofuran was added to the reaction mixture to crystallize. The resulting crystals were filtered to afford 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4 as the target compound. 31.46 g (86%) of warm, hydrochloride and dihydrate were obtained. The obtained product was analyzed to be the same material as obtained in Example 5.

(Example 8)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

Acetonitrile 19.93 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 20.1 g of 1- (N, N-diethylaminomethyl) -2-methylimidazole After addition to 200 ml, 10 ml of methanesulfonic acid were added. The temperature of the reaction was slowly raised to 90 ° C. and heated to reflux for 8 hours. The reaction was cooled to 5 degrees and 200 ml of hexane was added to the reaction to give a precipitate. The resulting crystals were filtered to afford the crude product 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4 35.8 g of -on methanesulfonic acid salt were obtained. The obtained crystals were dissolved in 100 ml of 1N sodium hydroxide and extracted with 200 ml of chloroform. The chloroform solution was washed with water, dried over anhydrous magnesium sulfate, decolorized and filtered using 2 g of activated carbon. The solvent in the filtrate was distilled off under reduced pressure and 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole as a residue 24.3 g (83%) of 4-one were obtained.

Melting Point (℃): 231-232

Purity (HPLC): 99%

¹ H-NMR (DMSO-d 6) (ppm): (1.75 to 1.88 (m, 1H), 2.00 to 2.10 (m. 1H), 2.31 (s, 3H),

2.83 to 3.19 (m, 3H), 3.72 (s, 3H), 4.08 (dd, 1H), 4.44 (dd, 1H), 6.74 (s, 1H), 7.07 (s, 1H), 7.24 (m, 2H) , 7.54 (d, 1H), 8.03 (d, 1H))

(Example 9)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

16.70 g of 1- (N, N-dimethylaminomethyl) -2-methylimidazole and 19.93 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one were added to dimethylformamide. After addition to 200 ml, 10 ml of formic acid was added dropwise. The reaction was heated at 80 ° C. for 8 hours and the reaction was complete and then cooled to 5 ° C. 200 ml of hexane was added to the reaction solution to crystallize. The resulting crystals were filtered and dissolved in 100 ml of 1N-sodium hydroxide solution. The extract was extracted with 200 ml of chloroform and the chloroform solution was washed with water, dried over anhydrous magnesium sulfate and activated charcoal, and decolorized and filtered. The solvent of the obtained filtrate was distilled off under reduced pressure and 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carba as a residue 23.8 g (81%) of sol-4-one were obtained. The obtained compound was confirmed to be the same compound as the obtained compound in Example 8.

(Example 10)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

19.93 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one was dissolved in 200 ml of acetonitrile. To the solution was added 13.34 g of anhydrous aluminum chloride, followed by 16.70 g of 1- (N, N-dimethylaminomethyl) -2-methylimidazole prepared in Example 1. The reaction was reacted for 8 hours while heating to reflux. The reaction was cooled to 0 ° C. The solvent of the reaction solution was distilled off under reduced pressure, and then 200 ml of chloroform and 100 ml of 0.2N sodium hydroxide solution were added to the residue. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in hot methanol, crystallized, filtered and dried to give 22.88 g (78%) of the title compound. The obtained compound was confirmed to be the same compound as the obtained compound in Example 8.

(Example 11)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

1.993 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one was dissolved in 20 ml of toluene. To the solution was added 1.334 g of anhydrous aluminum chloride, followed by 1.67 g of 1- (N, N-dimethylaminomethyl) -2-methylimidazole prepared in Example 1. Subsequently, the same procedure as in Example 10 was carried out to obtain 2.20 g (75%) of the title compound. The obtained compound was confirmed to be the same compound as the obtained compound in Example 8.

(Example 12)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

19.93 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one was dissolved in 200 ml of tetrahydrofuran. To the solution was added 13.0 g of boron trifluoride-methylsulfide complex, followed by 31.0 g of 1- (N, O-dimethylhydroxyamino) -2-methylimidazole prepared in Example 3. The reaction was reacted for 8 hours while heating to reflux. The reaction was cooled to 0 ° C. The solvent of the reaction solution was distilled off under reduced pressure, and then 200 ml of chloroform and 100 ml of 0.2N sodium hydroxide solution were added to the residue. The organic layer was separated, washed twice with the same amount of water, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was dissolved in hot methanol, crystallized, filtered and dried to give 23.4 g (80%) of the title compound. The obtained compound was confirmed to be the same compound as the obtained compound in Example 8.

(Example 13)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

19.93 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 20.1 g of 1- (N, N-diethylaminomethyl) -2-methylimidazole and anhydrous tetrachloride 26.1 g of tin was used, and methylene chloride was used as a solvent to carry out the same procedure as in Example 10 to obtain 22.0 g (75%) of the title compound. The obtained compound was confirmed to be the same compound as the obtained compound in Example 8.

(Example 14)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one 29.36 g in 20 ml of 6N- Dissolved in hydrochloric acid. After completely dissolved, 2 g of activated carbon was added, stirred for 30 minutes, and filtered. The filtrate was crystallized by slowly dropwise addition to 150 ml of ethanol, which was kept at 5 degrees and stirred well. After the addition was completed, stirring was continued for 3 hours while maintaining the same temperature. The resulting crystals were filtered off, washed with a small amount of ethanol and then vacuum dried at 20 degrees Celsius for 24 hours to give 32.9 g (90%) of the desired product.

Melting Point (℃): 178.5-179.5

¹ H-NMR (DMSO-d 6) (ppm): (1.88 to 2.06 (m, 1H), 2.10 to 2.23 (m. 1H), 2.65 (s, 3H),

2.95 to 3.23 (m, 3H), 3.74 (s, 3H), 4.27 (dd, 1H), 4.65 (dd, 1H), 7.20 (m, 2H), 7.56 (m, 2H), 7.67 (d, 1H) , 8.00 (d, 1H))

Water (Karlfisher): 9.95% (Theoretical: 9.85%)

According to the preparation method of the invention, 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4- On (ondansetron) and its pharmaceutically acceptable salts can be prepared in high yield, high purity in a simple and economical process.

Claims (7)

To the 1- (substituted methyl) -2-methylimidazole derivative of the formula (2) and 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of the formula (3) 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl]-of formula (1) characterized by reaction in the presence of an acid catalyst Method for preparing 4H-carbazol-4-one or a pharmaceutically acceptable salt thereof (Formula 1) (Formula 2) (Formula 3) Wherein R ¹ is R ² R ³ N-, 1-morpholinyl, or halogen, and R ² and R ³ are each C ₁ -C ₅ lower alkyl, benzyl, or alkoxy, or R ² and R ³ Together represent C ₁ -C ₅ cyclicalkyl. A compound according to claim 1, wherein the compound of formula (2) is 1- (N, N-dimethylaminomethyl) -2-methylimidazole, or 1- (N, N-diethylaminomethyl) -2-methyl Midazole, or 1- (N-morpholinyl) -2-methylimidazole, or 1- (N, O-dimethylhydroxyaminomethyl) -2-methylimidazole, or 1- (N, N Benzylmethylamino) -2-methylimidazole. The process according to claim 1, wherein the acid catalyst is hydrochloric acid, methanesulfonic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, chlorosulfonic acid, sulfuric acid, or hexanoic acid. The production process according to claim 1, wherein the acid catalyst is aluminum chloride, zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, ferric chloride, titanium chloride, or aluminum oxide. The process according to claim 1, wherein the acid as a catalyst is used in an amount of 0.1 to 5 equivalents based on the compound of the formula (3). A process according to claim 1, wherein 1 to 10 equivalents of the compound of formula (2) is used relative to the compound of formula (3). The method according to claim 1, wherein the reaction temperature is between 150 degrees at room temperature and the reaction time is performed at 2 to 24 hours.