Background of the Invention 1, 2,3, 9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazole-1-yl) methyl]-4H- carbazol-4-one or its salt is a useful compound as an anti-vomiting agent due to its selective action on 5-HT3 receptor, which is represented by the following chemical structure: The compound of formula 1 may be prepared by various methods, for example, as disclosed in GB Pat. No. 2,153, 821, EP Pat. No. 219,929, EP Pat. No.

221,629, KR Pat. No. 0217466, KR Pat. No. 216422, KR Pat. No. 0377578, and KR Pat. Pub. No. 2002-0039223 (corresponding to EP Pub. No. 1207160).

The process disclosed in GB Pat. No. 2,153, 821 may be summarized as following reaction scheme 1:

However, the above processes have the problems that the processes are completed through so many steps, which take so long time for carrying out the reactions of each step, and the yield of final product is very low.

The process disclosed in EP Pat. No. 219,929 may be summarized as following reaction scheme 2: In the above reaction, an anhydrous condition is required in order to introduce a dimethylamino group. Further, the process is completed through so many steps and employs an expensive agent. Accordingly, the process disclosed in EP Pat. No. 219,929 has difficulties to be applied to an industrial-scale mass production.

The process disclosed in EP Pat. No. 221,629 may be summarized as following reaction scheme 3:

However, the above process also has difficulties to be applied to an industrial-scale mass production in that the yield of final product is very low and the process employs very expensive catalyst.

The process disclosed in KR Pat. No. 0217466 may be summarized as following reaction scheme 4: However, the above process has the problems that the process employs excess acetic acid in order to prepare the compound of formula 2, which makes it difficult to carry out a work-up process after completion of reaction, and an additional isolation process is necessary in order to remove impurities.

KR Pat. No. 0217466 discloses a process for preparing the compound of formula 1, which comprises reacting the compound of formula 2 with an acid salt of 2-methyl imidazole. However, the reaction described in KR Pat. No. 0217466 is <BR> <BR> carried out at a high temperature, i. e. , above 130 °C, which is unfavorable for industrial-scale mass production.

The process disclosed in KR Pat. No. 0377578 and KR Pat. Pub. No. 2002- 0039223 (corresponding EP 1207160 Al) may be summarized as following reaction scheme 5:

The above process has the problem that the process requires an additional reaction step in order to prepare the starting material of formula 16, which have to be isolated by high vacuum distillation. Accordingly, the above process has difficulties to be applied to an industrial-scale mass production.

Disclosure of the Invention The present invention provides an improved process for preparing 1,2, 3,9- tetrahydro-9-methyl-3- [(2-methyl-1 H-imidazole-1-yl) methyl] -4H-carbazol-4-one or its salt in high purity and yield under a mild condition, so as to be favorably applied to a large-scale mass production thereof.

In one aspect of the present invention, there is provided a process for preparing a compound of formula 1, which comprises: (a) reacting a compound of formula 3 with a compound of formula 4, in a solvent, in the presence of an acidic medium to obtain a compound of formula 2; and (b) reacting the compound of formula 2 obtained in the step (a) with a compound of formula 5, in a solvent, in the presence of a clay as a catalyst, or with a compound of formula 6 in the presence of a halide compound as a catalyst:

wherein, n is 0 or 1, if n is 0, R', R, R3 and R4 are each independently a C1_6 alkyl or phenyl group,-(CH2) m ring or-(CH2) a-X-(CH2) b ring, wherein m, a and b are each independently 1 to 5 ; X is N, O or S, and if n is 1, Rl, R2 and R5 are each independently a C, 6 alkyl or aryl group; and R3 and R4 are each independently- CH2-group, and R6, R7 and R8 are each independently a Cl 6 alkyl or aryl group.

The above and other features and advantages of the present invention will become more apparent by describing in detail a preferred embodiment thereof.

Best mode for carrying out the Invention In accordance with the present invention, a compound of formula 1 or its salt can be prepared in high purity and yield under a mild condition by reacting a

compound of formula 3 with a compound of formula 4, in a solvent, in the presence of an acidic medium to obtain a compound of formula 2; and (b) (i) reacting the compound of formula 2 obtained in the step (a) with a compound of formula 5, in a solvent, in the presence of a clay as a catalyst, or (ii) reacting the compound of formula 2 obtained in the step (a) with a compound of formula 6 in the presence of a halide compound as a catalyst The inventive process may be represented by the following Reaction Scheme 6: wherein n, Rl, R2, R3, R4, R5, R6, R and R are the same as defined above.

Specifically, in the inventive process, the compounds of formula 3 and formula 4, which are starting material in the process of the present invention, may be prepared by a method which is known in the art (J. Org. Chem. 45, 2938 (1980); Synthesis, 215, (1990); Tetrahedron 53, 2941 (1997); Perkin Trans, I., J. Chem. Soc, 2117 (1989); Org. Syn., coll VI, 474; and J Org. Chem. 65, 8384 (2000) ), or it is commercially available.

The use of such reaction materials can make it to solve the problems of conventional techniques that require many reaction steps and an excessive amount of formaldehyde and acid in preparing the compound of formula 2, and to efficiently prepare the compound of formula 2 as an intermediate in high yield and purity.

In the step (a), representative examples of the compound of formula 4 may include (if n=0) N, N, N', N'-tetramethyldiaminomethane, N, N, N', N'-

tetraethyldiaminomethane, N, N, N', N'-tetrabutyldiaminomethane, dipiperidinomethane, 1, l'-methylenebis (3-methylpiperidine) and 4,4'- methylenedimorphorine; and (if n=l) 1, 3, 5-tribenzylhexahydro-1, 3,5-triazine, 1, 3, 5-triethylhexahydro-1, 3, 5-triazine and 1, 3, 5-trimethylhexahydro-1, 3,5-triazine.

The amount of the compound of formula 4 is preferably in the range of about 0. 3-10 eq. , more preferably 1-5 eq. , based on the amount of the compound of formula 3.

In the step (a), the acidic medium may be selected from the group consisting of chlorotrimethylsilane, trichloromethylsilane, acetic acid, acetic anhydride, trifluoroacetic acid, acetylchloride and a mixture thereof. The amount of the acidic medium is preferably in the range of about 0. 1-10 eq. , more<BR> preferably 0. 5-5 eq. , based on the amount of the compound of formula 4.

In the step (a), a base may be added to the reaction mixture during the reaction in order to raise the reaction rate and improve yield, representative examples thereof including, not limited to, triethylamine, pyridine, sodium acetate, potassium acetate, potassium carbonate and sodium carbonate. The amount of the base is preferably same as the amount of the acid used.

In the step (a), the solvent may be selected from the group consisting of acetonitrile, ethylacetate, tetrahydrofuran, toluene, 1, 4-dioxane, dimethylformamide and a mixture thereof.

In the step (a), the reaction may be performed preferably under reflux.

Accordingly, the reaction temperature in the step (a) is dependent on a solvent employed. The reaction may be completed preferably in about 1 ~ 24 hours.

The compound of formula 2 obtained in the step (a) may be used in a following reaction without an additional purification process.

In accordance with the step (b-i) of the present invention, the compound of formula 1 may be prepared by reacting the compound of formula 2 with a compound of formula 5, in a solvent, in the presence of clay as a catalyst.

The compound of formula 5 is commercially available. The amount of the compound of formula 5 is preferably in the range of about 1 ~ 10 eq. , more

preferably 1-5 eq. , based on the amount of the compound of formula 2.

A clay is a useful catalyst in solving the problems that, in the amine- addition reaction to exocyclic cL 13-unsaturated ketone, the reactivity between the reaction materials is low, which makes it long-reaction time and low-yield. Besides, the clay has many advantages of high-stability, low-price, recycle-potentiality, no <BR> <BR> toxicity, convenience in handling, quality stability, etc. , and thus it can be favorably applied to a large-scale mass production of the compound of formula 1.

In the step (b-i), Montmorillonite KSF or Montmorillonite K10 (products of Aldrich) may be preferably used as a clay catalyst. After completion of reaction, the clay may be removed by filtering or re-used. The amount of the clay is preferably in the range of about 1-500 wt%, more preferably about 10- 200 wt%, based on the amount of the compound of formula 2.

In the step (b-i), the solvent may be selected from the group consisting of toluene, xylene, benzene, 1,4-dioxane, heptane and a mixture thereof. The reaction in the step (b-i) may be performed preferably in reflux. Accordingly, the reaction temperature is dependent on the solvent employed. The reaction may be completed preferably in about 1 ~ 12 hours.

As an alternative method, in accordance with the step (b-ii) of the present invention, the compound of formula 1 may be prepared by reacting the compound of formula 2 with a compound of formula 6 in the presence of a halide compound as a catalyst.

The compound of formula 6 may be prepared by a method which is known in the art (Can. J. Chem. 58, 60,1980), representative examples thereof including trimethylsilylimidazole and t-butyldimethylsilylimidazole. The amount of the <BR> <BR> compound of formula 6 is preferably in the range of about 1 ~ 10 eq. , more<BR> preferably about 1. 5-6 eq. , based on the amount of the compound of formula 2.

In the step (b-ii), the halide compound as a catalyst may be preferably a quaternary ammonium halide, representative examples thereof including, not limited to, tetrabutylammonium fluoride. The amount of the halide compound is preferably in the range of about 0. 05 ~ 1 eq. based on the amount of the compound

of formula 2.

The reaction of the step (b-ii) is preferably carried out in the presence of a solvent. The solvent may be selected from the group consisting of acetonitrile, ethylacetate, tetrahydrofuran, toluene, 1,4-dioxane, dimethylformamide and a mixture thereof. However, the reaction may be carried out without the solvent. The reaction in the step (b-ii) may be performed preferably in reflux. Accordingly, the reaction temperature in the step (b-ii) is dependent on the solvent employed. The reaction may be completed preferably in about 0. 5-6 hours.

The present invention is further illustrated and described by the following examples, which should not be taken to limit the scope of the invention.

Synthesis of 12, 3 9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one Example 1 To the solution of 10 ml of acetic anhydride and 3.93 g of acetyl chloride in 40 ml of acetonitrile, was slowly added 6.82 ml of N, N, N', N'- tetramethyldiaminomethane. 2 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one was added to the reaction mixture, which was then stirred under reflux for 1 hour.

4. 1g of sodium acetate was added to the reaction mixture, which was then stirred under reflux. After completion of reaction, ethyl acetate was added to the reaction mixture, which was consequently washed with diluted HCI, saturated aqueous sodium bicarbonate solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate and evaporated to give 1.69 g of the title compound, which was used for next step without purification (yield 80%).

Example 2 The same procedures as described in Example 1 were repeated, except that 4.43 ml of N, N, N', N'-tetraethyldiaminomethane was employed instead of N, N, N', N'-tetramethyldiamino- methane, to give 1.77g of the title compound (yield 84%).

Example 3 The same procedures as described in Example 1 were repeated, except that 4.47 ml of dipiperidinomethane was employed instead of N, N, N', N'- tetramethyldiaminomethane, to give 1.90 g of the title compound (yield 90%).

Example 4 The same procedures as described in Example 1 were repeated, except that 5.33 ml of 1, 1-methylenebis (3-methylpiperidine) was employed instead of N, N, N', N'-tetramethyldiamino- methane, to give 1.90 g of the title compound (yield 90%).

Example 5 2g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one was added in 20 ml of acetic anhydride, and then the reaction mixture was heated to 100°C. 15 ml of N, N, N', N'-tetramethyldiaminomethane was added dropwise for 1.5 hours.

After completion of reaction, excess acetic anhydride was distilled off, and then ethyl acetate was added to the resulting residue, and then successively washed with diluted HCI, saturated aqueous sodium bicarbonate solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate and evaporated to give 1.50 g of the title compound, which was used for next step without purification (yield 70%).

Example 6 To a solution of 3.9 g of 1, 3, 5-trimethylhexahydro-1, 3,5-triazine in 40ml of toluene, was slowly added 3.4 g of trifluoroacetic acid at 0°C. The reaction mixture was stirred for 30 min at the same temperature. 2 g of 1, 2,3, 9-tetrahydro-9-methyl- 4H-carbazol-4-one was added to the reaction mixture, which was then stirred under reflux for 24 hours. After completion of reaction, the reaction mixture was evaporated and diluted with ethyl acetate, and then successively washed with

diluted HCI, saturated aqueous sodium bicarbonate solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting solid was purified with acetonitrile to give 1.30 g of the title compound (yield 62%).

Example 7 To a solution of 2.2 ml of acetyl chloride in 40ml of acetonitrile was, added dropwise 4.1 ml of N, N, N', N'-tetramethyldiaminomethane at 0°C, which was then stirred for 1 hour. 2 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one was added to the reaction mixture, which was then stirred under reflux for 2 hours. 2.46 g of sodium acetate was added to the reaction mixture, which was then stirred under reflux for 6.5 hours. After completion of reaction, acetonitrile was distilled off and the water was added to the resulting residue. The resulting solid was stirred for 1 hour, filtered and dried to give 1.9 g of the title compound (yield 90%).

Synthesis of 1,2, 3,9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-1-yl) methylL 4H-carbazol-4-one Example 8 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one prepared in any one of Examples 1 to 7,5. 89 g of 2-methyl imidazole and 1 g of montmorillonite K10 were added to 100ml of toluene, and then the reaction mixture was stirred under reflux for 6 hours. After completion of reaction, the solvent was distilled off, and then chloroform was added to the resulting residue and the catalyst was filtered off. The filtrate was washed with water, dried over anhydrous magnesium sulfate, and evaporated. The resulting solid was purified with ethyl acetate to give 6.94 g of the title compound as white solid (yield 99%).

Example 9 The suspension of 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H- carbazol-4-one prepared in any one of Examples 1 to 7,5. 89 g of 2-methyl imidazole and 1 g of montmorillonite KSF in 100ml of toluene was stirred under reflux for 6 hours. After completion of reaction, the reaction solvent was distilled off, and then chloroform was added to the resulting residue, and then the catalyst was filtered off. The filtrate was washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness. The resulting solid was purified with ethyl acetate to give 6.3 g of the title compound as white solid (yield 90%).

Example 10 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one prepared in any one of Examples 1 to 7 and 11 g of 2-methyl-1-trimethylsilyl imidazole was suspended in 25 ml of acetonitrile. 23. 7ml of 1N tetra-n- butylammonium fluoride solution was added dropwise for 10 min under reflux, and then the reaction mixture was stirred for 2 hours. After cooling to room temperature, 100 ml of water was added to the reaction mixture, and then stirred for 30 min. The resulting solid was filtered and washed with 100 ml of water to give 5.85 g of the title compound as a white solid (yield 84.2%).

Example 11 The same procedures as described in Example 10 were repeated, except that tetrahydrofuran was employed instead of acetonitrile, to give 6.14 g of the title compound (yield 88.3%).

Example 12 The same procedures as described in Example 10 were repeated, except that 1.4-dioxane was employed instead of acetonitrile, to give 5.56 g of the title compound (yield 80%).

Example 13 The same procedures as described in Example 10 were repeated, except that toluene was employed instead of acetonitrile, to give 6.32 g of the title compound (yield 91%).

Example 14 5g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one prepared in any one of Examples 1 to 7 and llg of 2-methyl-l-trimethylsilyl imidazole were suspended in 25 ml of acetonitrile. 1. 9ml of IN tetra-n- butylammonium fluoride solution was added dropwise for 10 min under reflux, and then the reaction mixture was stirred for 2 hours. After cooling to room temperature, 100 ml of water was added to the reaction mixture, and then stirred for 30 min. The resulting solid was filtered and washed with 100 ml of water to give 5.85 g of the title compound as a white solid (yield 87%).

Example 15 The mixture of 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H- carbazol-4-one prepared in any one of Examples 1 to 7 and 11 g of 2-methyl-1- trimethylsilyl imidazole was heated to 80 °C. 23.7 ml of IN tetra-n- butylammonium fluoride solution was added dropwise for 10 min under reflux, and then the reaction mixture was stirred for 2 hours. After cooling to room temperature, 100 ml of water was added to the reaction mixture, and then stirred for 30 min. The resulting solid was filtered and washed with 100 ml of water to give 6.2 g of the title compound as a white solid (yield 92%).

Example 16 The mixture of 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H- carbazol-4-one prepared in any one of Examples 1 to 7 and 22 g of 2-methyl-1- trimethylsilyl imidazole was heated to 80°C. 2. 37ml of IN tetra-n-butylammonium fluoride solution was added dropwise for 10 min under reflux, and then the

reaction mixture was stirred for 2 hours. After cooling to ambient temperature, 100 ml of water was added to the reaction mixture, and then stirred for 30 min. The resulting solid was filtered and washed with 100 ml of water to give 6.61 g of the title compound as a white solid (yield 98%).

Example 17 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one prepared in any one of Examples 1 to 7 and 11 g of 2-methyl-l-trimethylsilyl imidazole were suspended in 35 ml of acetonitrile. The solution of 6.2 g of tetra-n- butylammonium fluoride hydrate in 15 ml of acetonitrile was added dropwise for 10 min under reflux, and then the reaction mixture was stirred for 2 hours. After cooling to ambient temperature, the reaction solvent was distilled off. 100 ml of water was added to the residue, and then stirred for 30 min. The resulting solid was filtered and washed with 100 ml of water to give 6.61 g of the title compound as a white solid (yield 98%).

Example 18 The same procedures as described in Example 17 were repeated, except that tetrahydrofuran was employed instead of acetonitrile, to give 6.57 g of the title compound (yield 94.5%).

Example 19 The same procedures as described in Example 17 were repeated, except that ethyl acetate was employed instead of acetonitrile, to give 6.72 g of the title compound (yield 96.7%).

Example 20 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one prepared in any one of Examples 1 to 7 and 22 g of 2-methyl-l-trimethylsilyl imidazole were suspended in 35 ml of acetonitrile. The solution of 6.2 g of tetra-n-

butylammonium fluoride hydrate in 15 ml of acetonitrile was added dropwise for 10 min under reflux, and then the reaction mixture was stirred for 2 hours. After cooling to ambient temperature, the reaction solvent was distilled off. 100 ml of water was added to the residue, and then stirred for 30 min. The resulting solid was filtered and washed with 100 ml of water to give 6.75 g of the title compound as a white solid (yield 100%).

Example 21 To the mixture of 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-methylene-4H- carbazol-4-one prepared in any one of Examples 1 to 7 and 22 g of 2-methyl-1- trimethylsilyl imidazole was added 6.2 g of tetra-n-butylammonium fluoride hydrate at 80 °C, and then the reaction mixture was stirred for 2 hours. After cooling to ambient temperature, 100 ml of water was added to the reaction mixture, and then stirred for 30 min. The resulting solid was filtered and washed with 100 ml of water to give 6.48 g of the title compound as a white solid (yield 96. 1%).

Synthesis of 12 3 9-tetrahedro-9-methyl-3- [(2-methyl-1 H-imidazol-1-yl ! methyll- 4H-carbazol-4-one hydrochloride dihydrate Example 22 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-1-yl) methyl]- 4H-carbazol-4-one obtained in Example 8 was suspended in 50 ml of ethanol and 5 ml of water. 1.9 g of conc. HCl was slowly added to the suspension, which was then stirred for 30 min at room temperature. The reaction mixture was dissolved at 70 °C, and then filtered to remove insoluble impurities. The reaction mixture was cooled to room temperature, and solidified for 3 hours. The resulting solid was filtered, washed with cold ethanol, and then dried in vacuous at 25 °C to give 5.3 g of a pure title compound as white solid (yield 85%).

Example 23 6 g of 1, 2,3, 9-tetrahydro-9-methyl-3- [ (2-methyl-1H-imidazol-1-yl) methyl] - 4H-carbazol-4-one obtained in Example 21 was suspended in 60 ml of ethanol and 6 ml of water. 2.1 g of conc. HCl was slowly added to the suspension, which was then stirred at room temperature for 30min. The reaction mixture was dissolved at 70 °C, and then filtered to remove insoluble impurity. The mixture was cooled to ambient temperature, and solidified for 3 hours. The resulting solid was filtered, washed with cold ethanol, and then dried in vacuous at 25 °C to give 6.51 g of a pure title compound as a white solid (yield 87%).

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made by those skilled in the art, which also fall within the scope of the invention as defined by the appended claims.