MX2007012644A - Novel process for producing ramosetron or its salt. - Google Patents

Abstract

[PROBLEMS] To provide a novel process for producing ramosetron or its salt that is useful as a pharmaceutical, especially as a therapeutic and/or preventive agent for digestive symptoms caused by administration of an anti-malignant tumor agent, diarrheal-type irritable bowel syndrome, diarrheal symptoms of irritable bowel syndrome, etc. [MEANS FOR SOLVING PROBLEMS] Ramosetron or its salt can be produced by reacting any of compounds of the formula: (I) [wherein X is a halogen] or a salt thereof with 1-methyl-1H-indole in the presence of a Lewis acid selected from the group consisting of lower-alkylaluminum dihalides, di-lower-alkylaluminum halides, tri-lower-alkylaluminums and lower-alkylaluminum sesquihalides.

Description

NEW PROCESS TO PRODUCE RAMOSETRON OR UMA SALTA DEL SISMO Field of the Invention The present invention relates to a novel process for producing ramosetron or a salt thereof which is useful as a pharmaceutical product, especially as a 5-HT3 receptor antagonist, more specifically, a therapeutic agent and / or preventive agent for digestive symptoms (nausea, emesis) caused by the administration of a malignant antitumor agent (cisplatin or the like), irritable bowel syndrome of diarrheal type, diarrheal symptoms of irritable bowel syndrome, and the like. Background of the Invention The chemical name of the ramosetron is (-) - (R) -5 - [(1-methyl-1 H-indol-3-yl) carbonyl] -4,5,6,7-tetrahydro-1 H -benzimidazole, and has the structure represented by the formula (II).

It is known that the ramosetron or a salt thereof has a potent 5-HT3 receptor antagonism (Patent Reference 1, Non-Patent References 1 and 2), and is on the market as a preventive or therapeutic agent for digestive symptoms (nausea, emesis) caused by the administration of a malignant antitumor agent (cisplatin or the like). In addition, one possibility has been described that the ramosetron or a salt thereof may be used as an agent for treating diarrheal irritable bowel syndrome or an agent for improving the diarrheal symptoms of irritable bowel syndrome (Patent Reference 1), and his clinical tests are now progressing as an agent to treat diarrheal irritable bowel syndrome or an agent to improve the diarrheal symptoms of irritable bowel syndrome. As a process for producing the ramosetron or a salt thereof, the following production methods are known. Patent Reference 1 describes a production method shown by the following Production method A, ie a method for producing a tetrahydrobenzimidazole derivative (V) allowing a heterocyclic compound (III) to react with a carbohydric acid represented by a formula (IV) or its reactive derivative. (Production Method A) (In the formula, X2 is a single bond and links to a carbon atom in the heterocyclic ring represented by Het).

As the illustrative production method of the ramosetron, Patent Reference 1 discloses a production method (Production Method A-1) in which the racemic ramosetron is obtained using 1-methyl-1 H-indole as the compound (III) , and N, N-diethyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide or N - [(4,5,6,7-tetrahydrobenzimidazol-5-yl) carbonyl] pyrrolidine, which are acidic amides, as the reactive derivative of the compound (IV), which allows to undergo the treatment with phosphorus oxychloride (Vilsmeyer reaction), and then its optical resolution was performed by fractional crystallization using (+) - dibenzoyltartaric acid.

In addition, Patent Reference 1 exemplifies an acid halide as one of the reactive derivatives of the compound (IV), and also describes another method of producing the compound (V) (Production Method A-2) in which the heterocyclic compound (III) is condensed with an acid halide of the compound (IV) by the Friedel-Crafts acylation reaction using a Lewis acid as the catalyst. However, the example of illustrative production of the ramosetron by the Friedel-Crafts acylation reaction is not described herein. Also, a method similar to Production Example A-1 is described in the non-patent references 1 and 2 as a method of production of the ramosetron. In addition, the non-patent Reference 3 discloses a method for producing the 11C-labeled ramosetron, represented by a Production B method. However, it describes only the methylation step, and does not disclose a method of producing nor-YM060 as the material Of start. (Production Method B) (In the formula, nor-YM060 means (R) -5 - [(1 H-indol-3-M) carbonyl] -4,5,6,7,7-tetrahydro-1 H-benzimidazole which was provided by the present application , DMF means dimethylformamide). Patentless Reference 1: Chemical &; Pharmaceutical Bulletin, 1996, vol. 44, no. 9, p. 1707-1716. Reference without Patent 2: Drugs of the Future, 1992, vol. 17, no. 1 p. 28-29. Reference without Patent 3: Applied Radiation and Isotopes, 1995, vol. 46, no. 9, p. 907-910. Reference without Patent 1: JP-B-6-25153. Description of the Invention Problems that the Invention Solves The conventional production methods of ramosetron are not industrially satisfactory in terms of production efficiency. Therefore, the greatest interest has been directed towards the development of an efficient method to produce the ramosetron or a salt thereof, particularly a method to produce the ramosetron that does not cause racemization and can preserve the optical purity. Means for Problem Solving The present inventors have conducted extensive studies with a view to developing an industrially more efficient production method of ramosetron or a salt thereof. As a result, it was found that, according to the following production method, the ramosetron or a salt thereof can be produced with high efficiency with the progress of the reaction which hardly reduce its optical purity and can maintain its stereotimetry, consequently achieving the present invention. That is, according to the present invention, the novel production methods of ramosetron or a salt thereof are provided in the following. (1) (Production Method 1) A method for producing the ramosetron or a salt thereof, characterized in that a compound represented by a formula (I) [X in the formula represents a halogen] or a salt thereof allowing to react with 1-methyl-1 H-indole in the presence of a Lewis acid selected from the group consisting of a lower alkylaluminum dihalide, a di-alkylaluminum halide lower, a lower tri-alkylaluminum, and a lower alkylaluminum sesquihalide. (2) (Production Method 2) A method for producing the ramosetron or a salt thereof, characterized in that a compound represented by the formula (I) described in (1) is prepared leaving the acid (R) -4.5. , 6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid or a salt thereof, reacting with a halogenating agent, and then allowing to react with 1-methyl-1 H-indole in the presence of a Lewis acid selected from the a group consisting of a lower alkylaluminum dihalide, a lower di-alkylaluminum halide, a lower tri-alkylaluminum, and a lower alkylaluminum sesquihalide. (3) The production method described in (1) or (2), wherein the Lewis acid is diethylaluminum chloride or diethylaluminum sesquichloride. (4) The production method described in (3), wherein the solvent of the reaction is an aromatic hydrocarbon. (5) The production method described in (4), wherein the aromatic hydrocarbon is toluene. (6) The ramosetron or a salt thereof produced by the production method described in (1). (7) The ramosetron or a salt thereof produced by the production method described in (2). In addition, according to the present invention, the composition shown below, comprising the ramosetron or a salt thereof, is also provided. (8) A composition comprising the ramosetron or a salt thereof, characterized in that it contains 5 - [(1-methyl-1 H -indol-5-yl) carbonyl] -4,5,6,7-tetrahydro-1 H-benzimidazole or a salt thereof and / or 5 - [(1-methyl-1 H -indol-6-yl) carbonyl] -4,5,6,7-tetrahydro-1 H-benzimidazole or a salt thereof , in a total amount of less than 1% based on the ramosetron or a salt thereof. Advantage of the Invention Since the reaction in the production method of the present invention progresses by maintaining the stenochemetry, as described below, the ramosetron or a salt thereof having high optical purity can be produced with a high acid yield ( R) -4,5,6,7-tetrahydro-1 H-benzimidazole-5-carboxylic acid or a salt thereof which is conventionally known and can be easily produced. On the one hand, in the production method A-1 described in Patent Reference 1, the ramosetron is produced by condensing an acid amide compound and 1-methyl-1 H-indole by the Vilsmeyer reaction and then performing the optical resolution by fractional crystallization using (+) - dibenzoyltartaric acid. However, when the optical resolution was prepared after the stage of the production process, it becomes necessary to overuse the material for the production of the unnecessary optical isomer that occupies half a part.

However, even when an optically active acid amide compound is used as the starting material in the production method A-1, it is racemized completely in the Vilsmeyer reaction step, so that it becomes necessary to carry out a treatment to increase the optical purity after the reaction, to obtain the ramosetron which has a high optical purity. On the other hand, according to the method of the present invention, the reaction proceeds with a high yield while maintaining the stoichiometry, so that the ramosetron having a high optical purity can be efficiently produced from the optically active compound (I) industrially. In addition, 1,2-dichloroethane is used in production method A-1 as the solvent in the Vilsmeyer reaction stage, but is now considered not to be used in the production of pharmaceutical preparations. On the other hand, toluene is suitably used in the production method of the present invention. further, in the production of the ramosetron hydrochloride currently produced by the applicant by the production method A-1, the crystals containing the ramosetron were filtered 6 times in total in the stages of incorporation and purification of the racemic bodies of the ramosetron, the ramosetron of (+) -dibenzoyltartarate and ramosetron hydrochloride, in order to obtain the ramosetron hydrochloride which has a high optical purity. On the other hand, as described below, the ramosetron hydrochloride having a high optical purity can be obtained once or twice by the production method of the present invention, including its purification, filtration, so that the handling is convenient. Also, the production method A-2 is a method for producing a tetrahydrobenzimidazole derivative (V) allowing a heterocyclic compound (III) and an acid halide of the compound (IV) to undergo the Friedel-Crafts acylation reaction using a Lewistic acid as the catalyst. However, as described above, an example of illustrative production of the ramosetron by this production method is not described herein. Also, Patent Reference 1 describes, as an example of production of the analogous compounds, a method for producing 5 - [(benzothiophen-3-yl) carbonyl] -4,5,6,7-tetrahydrobenzimidazole and 5- [(2-methylbenzofuran-3-yl) carbonyl] -4,5,6,6-tetrahydrobenzimidazole by the Friedel-Crafts acylation reaction using respectively aluminum tetrachloride and tin chloride as the Lewis acid, but it can not be said that their returns are adequate. Furthermore, when the same reaction conditions were applied to the production of the ramosetron, the yield was also low, and its purification was difficult to perform due to the production of a highly viscous tarred substance. Thus, Lewis acids that are generally and frequently used in the production of the ramosetron can not be industrially used. Accordingly, the present inventors have examined extensively in Lewis acids and, as a result, have unexpectedly found that the ramosetron can be produced with fewer byproducts and high yield when a lower alkylaluminum dihalide, a lower alkylaluminum halide, a tri -alkylaluminum and a lower alkylaluminum sesquihalide were used as Lewis acids. Furthermore, in the case of the production of the ramosetron using the Lewis acids to be used in the present invention, it was unexpectedly revealed that the reaction progresses hardly by reducing the optical purity while maintaining the stenochemistry when the reaction is carried out using the optically active compound ( I). Based on this, according to the production method of the present invention, the ramosetron having a high optical purity can be industrially produced efficiently from the optically active compound (I).

In addition, the labeled ramosetron is produced in production method B, by methylation of an optically active compound (V) with the labeled methyl iodide. However, production method B is a production method that requires nor-YM060 to mark the position 1 of the indole, so that the process becomes longer than the production method of the ramosetron, by a stage factor. 1. On the other hand, according to the present invention, the number of stages can become short due to the production that does not require nor-YM060.

Accordingly, the production method of the present invention is a superior production method compared to conventional production methods, in terms of (1) high yield, (2) avoid the use of solvents that should not be used in producing preparations pharmaceuticals, (3) less environmental burden, (4) shortened number of total stages and (5) improved convenience of handling. BEST MODE FOR CARRYING OUT THE INVENTION The additional description in the present invention is as follows. In this description, "alkyl" means a straight or branched saturated aliphatic hydrocarbon chain. "Lower alkyl" means an alkyl of 1 to 6 carbon atoms. Illustrative examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl and the like. Methyl and ethyl are preferable. "Halogen" means F, Cl, Br and I. Cl is preferred. "Lower tri-alkylaluminum" means a compound represented by Al (lower alkyl) 3. Illustrative examples include trimethylaluminum, triethylaluminum and triisobutylaluminum. Trimethylaluminium is preferable. The "lower alkylaluminum dihalide" means a compound represented by Al (lower alkyl) (halogen) 2. Illustrative examples include methylaluminum dichloride and ethylaluminum dichloride. Ethyl aluminum dichloride is preferable.

The "lower di-alkylaluminum halide" means a compound represented by Al (lower alkyl) 2 (halogen). Illustrative examples include dimethylaluminum chloride and diethylaluminum chloride. Diethylaluminum chloride is preferable. The "lower alkylaluminum sesquihalide" means a compound represented by Al 2 (lower alkyl) 3 (halogen) 3. Illustrative examples include methylaluminum sesquichloride and ethylaluminum sesquichloride. Ethyl aluminum sesquichloride is preferable. The "aromatic hydrocarbon" as the solvent for the Friedel-Crafts acylation reaction can be any substance that can be used as the solvent for the Friedel-Crafts acylation reaction. Illustrative examples thereof include benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene and nitrobenzene. Toluene is preferable. The "salt thereof" in the "ramosetron or a salt thereof" can be any substance which is a salt of the ramosetron with an acceptable pharmaceutical acid. Illustrative examples thereof include an acid addition salt of the ramosetron with the inorganic acid such as hydrochloric acid, sulfuric acid or the like or with an organic acid such as acetic acid, oxalic acid, malonic acid, succinic acid or the like. As the "ramosetron or a salt thereof", ramosetron or ramosetron chloride is preferable. A generally used salt formation method can be used in salt formation. In addition, the present invention also includes a method for producing a compound, so-called labeled substance, in which a part or all of the atoms constituting the ramosetron and / or a production material thereof are replaced by a radioactive isotope. The production method 1 of the present invention is a method of producing the ramosetron in which the compound represented by the formula (I) and 1-methyl-1 H-indole is allowed to undergo the reaction of the Friedel-Crafts acylation in presence of a Lewis acid while maintaining the estequimetry. The reaction can be carried out using the production material in an equimolar base or one thereof in an excess amount under cooling to heating, where it is preferable to perform it under cooling. Since the solvent to be used in the reaction, no solvent can be used or an inert solvent for the reaction can be used, including aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene and the like, ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane (DME) and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and the like, acetonitrile, dimethyl sulfoxide (DMSO), ethyl acetate, N, N-dimethylformamide (DMF), nitromethane, carbon disulfide and the like , as well as a mixed solvent thereof. Aromatic hydrocarbons are preferable and toluene is more preferable. The Lewis acid can be used in an equivalent or excess amount, and is preferably diethylaluminum chloride or diethylaluminum sesquichloride. In addition, Cl is preferable as X in formula (I). The production method 2 of the present invention is a method of producing ramosetron in which (R) -4,5,6,7-tetrahydro-1 H-benzimidazole-5-carboxylic acid or a salt thereof is left reacting with a halogenating agent to obtain the compound represented by the formula (I), and then this and 1-methyl-1 H-indole is allowed to undergo the reaction of the Friedel-Crafts acylation in the presence of a Lewis acid while Stereochemistry is maintained. The first half of the halogenation reaction can be carried out using the production material in an equimolar base or one of them in an excess amount under cooling to heating under reflux, where it is preferable to carry it out under heating. The reaction can be performed without solvent or in a solvent inert to the reaction, including an aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene and the like, an ether such as diethyl ether, tetrahydrofuran, dimethoxyethane (DME) and the like, a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chloroform and the like, acetonitrile, ethyl acetate, N, N-dimethylformamide (DMF) and the like, or in a mixed solvent thereof. Tetrahydrofuran and dimethoxyethane are preferable. As the halogenating agent, halogenation agents generally used in the production of acid halides, such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide and the like can be used. Thionyl chloride is preferable. In addition, Cl is preferable as X in formula (I). With respect to the last Friedel-Crafts acylation average reaction, the reaction can be carried out by the same method of production method 1. The acid halide produced in the first half of the step can be used in the last half stage by isolating it or not. isolating it. According to the above-mentioned production method 1 or production method 2, a composition comprising the ramosetron or a salt thereof, containing benzimidazole of 5 - [(1-methyl-1 H-indol-5-yl) can be obtained carbonyl] -4,5,6,7-tetrahydro-1 H (hereinafter "compound A") or a salt thereof and 5 - [(1-methyl-1 H -indol-6-yl) carbonyl ] -4,5,6,7-tetrahydro-1 H-benzimidazole "B compound" or a salt thereof, in a total amount of less than 1% based on the ramosetron or a salt thereof. The content of percent of compound A or a salt thereof and compound B or a salt thereof based on the ramosetron or a salt thereof is preferably less than 0.5%, more preferably less than 0.2%, more preferably less than 0.1 %, based on ramosetron or a salt thereof. The composition obtained in this way, comprising the ramosetron or a salt thereof, can be used as a therapeutic agent and / or preventive agent for digestive symptoms (nausea, emesis) caused by the administration of a malignant antitumor agent (cisplatin or the like) Irritable bowel syndrome of diarrheal type, diarrheal symptoms of irritable bowel syndrome and the like. The structures of compound A and compound B are shown below.

Compound B Examples The following illustratively describes the present invention based on the examples, but the invention is not restricted by these examples. Example 1 Heating a mixture of 4.05 g of (R) -4,5,6,7-tetrahydro-1 H-be nimet id azol-5-carboxylic acid monohydrochloride (99.4% ee), 120 ml of dimethoxyethane and 5.47 g of thionyl chloride at 70 ° C for 2 hours, the chloride of (R) -4,5,6,7-tetrahydro-1 H-benzimidazole-5-carbonyl was synthesized, and the solvent was evaporated under reduced pressure. An 80 ml portion of toluene was added to the residue and evaporated again under reduced pressure, and the residue was mixed with 120 ml of toluene and 5.24 g of 1-methyl-1H-indole and cooled to -40 ° C in a nitrogen atmosphere. A 30 ml portion of 1.0 mol / l toluene solution of ethylaluminum sesquichloride was slowly added to this liquid and stirred at -40 ° C for 3 hours, and 10 ml of tetrahydrofuran were added after stirring. This liquid was slowly dispersed in 160 ml of water cooled to 0 ° C, and then the organic layer was removed, the water layer was washed with 40 ml of toluene and extracted by adding 80 ml of 2-butanone and 50 ml of water. % aqueous solution of sodium hydroxide to it. The water layer was washed with 40 ml of 2-butanone, and the organic layers were combined and washed twice with 20 ml of 10% brine and then with 4 ml of water. A 40 ml portion of ethanol was added to the organic layer thus obtained and evaporated under reduced pressure, and 40 ml of ethanol was added back to the residue and evaporated under reduced pressure. A 120 ml portion of a mixed solvent of ethanol and ethyl acetate (1: 3) was added to the residue, and this was heated at 70 ° C for 1 hour by adding 5 ml of the 4 mol / ethyl acetate solution. l of hydrogen chloride and then cooling slowly to 0 ° C. The precipitated crystals were filtered, and the crystals were washed with a mixed solvent of ethanol-ethyl acetate and then dried in vacuo at 50 ° C, thereby obtaining 4.98 g of (-) - (R) -5- monohydrochloride. [(1-methyl-1 H-indol-3-yl) carbonyl] -4,5,6,7-tetrahydro-1 H-benzimidazole (yield 78.8%, 99.5% ee). FAB-MS (m / z): 280 [M + H +] 1 H-NMR (DMSO-de, 30 ° C): d ppm (internal standard of TMS): 1.82-1.95 (1H, m), 2.12-2.22 ( 1H, m), 2.66-2.94 (4H, m), 3.63 -3.72 (1H, m), 3.88 (3H, s), 7.24 (1H, t, J = 15 8.0 Hz), 7.30 (1H, t, J = 8.0 Hz), 7.56 (1H, d, J = 8.0 Hz), 8.22 (1H, d, J = 8.0 Hz), 8.53 (1H, s), 8.90 (1H, s), 14.42 (1H, broad). Example 2 Heating a mixture of 4.05 g of (R) -4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid monohydrochloride (99.4% ee), 120 ml of dimethoxyethane and 5.47 g of chloride of thionyl at 70 ° C for 2 hours, the (R) -4,5,6,7-tetrahydro-1H-benzimidazole-5-carbonyl chloride was synthesized, and the solvent was evaporated under reduced pressure. An 80 ml portion of toluene was added to the residue and evaporated again under reduced pressure, and the residue was mixed with 120 ml of toluene and 5.24 g of 1-methyl-1H-indole and cooled to -25 ° C in an atmosphere of nitrogen. A 33 ml portion of 1.8 mol / l of the toluene solution of diethylaluminum chloride was slowly added to this liquid and stirred at -25 ° C for 2 hours, and further 8 ml of tetrahydrofuran was added after stirring. This liquid was slowly dispersed in 100 ml of water which was cooled to 0 ° C, and then heated to 45 ° C. After removing the organic layer, the water layer was washed with 40 ml of toluene, and this was extracted by adding 80 ml of 2-butanone and further 50 ml of 20% aqueous sodium hydroxide solution. The water layer was washed with 40 ml of 2-butanone, and the organic layers were combined and washed twice with 20 ml of 10% brine and then with 4 ml of water. The organic layer thus obtained was evaporated under a reduced pressure, 40 ml of ethanol was added to the resulting residue and evaporated under a reduced pressure and again vaporized under a reduced pressure., and again 40 ml of ethanol was added to the residue. A 120 ml portion of a mixed solvent of ethanol and ethyl acetate (1: 3) was added to the residue, and this was heated at 70 ° C for 12 hours by adding 5 ml of ethyl acetate solution of 4 mol / l. of hydrogen chloride and then cooled slowly to 0 ° C. The precipitated crystals were filtered and the crystals were washed with a mixed solvent of ethanol-ethyl acetate and then dried in vacuo at 50 ° C, thereby obtaining 5.45 g of the monohydrochloride of (-) - (R) -5- [ (1-methyl-1 H-indol-3-yl) carbonyl] -4,5,6,7-tetrahydro-1 H-benzimidazole (yield 86.3%, 99.2% ee). FAB-MS (m / z): 280 [M + H *]. 1 H-NMR (DMSO-d 6, 30 ° C): d ppm (internal standard of TMS): 1.82 - 1.95 (1H, m), 2.12 - 2.22 (1H, m), 2.66 - 2.94 (4H, m), 3.63 -3.72 (1H, m), 3.88 (3H, s), 7.24 (1H, t, J = 8.0 Hz), 7.30 (1H, t, J = 8.0 Hz), 7.56 (1H, d, J = 8.0 Hz) , 8.21 (1H, d, J = 8.0 Hz), 8.53 (1H, s), 8.91 (1H, s), 14.45 (1H, broad).

The percentage content of compound A and compound B, when the ramosetron in the composition containing the ramosetron obtained in Example 1 or Example 2 is considered as 100%, is shown in Table 1. In this connection, the determination of the compound A and compound B by liquid chromatography under the following conditions, and the maximum area was measured by an automatic integration method. The percentage content (%) of each compound = A / B [in the formula, A represents the maximum area of each compound in the sample, and B the maximum area of the ramosetron]. < Test Conditions > Detector: An ultraviolet absorption detector (254 nm measured wavelength) Column: Nomura Kagaku Develosil C8-5, 4.6 nm x 150 mm Column temperature: constant temperature at about 40 ° C of the mobile phase: aqueous solution of KH2PO4 0.05 M adjusted to pH 4.0 with H3PO4): MeOH: THF = 8: 1: 1 Flow Rate 0.82 ml / min.

When measured under the above conditions, the retention times of the ramosetron, compound A and compound B were approximately 7.41 minutes, approximately 9.45 minutes and approximately 11.91 minutes, respectively in Example 1, and approximately 7.01 minutes, approximately 9.00 minutes and approximately 12.46 minutes in Example 2.

Table 1 Percent content (%) of each compound The values of the physical properties of compound A and compound B are shown below. Compound A: LC-ESI: 280 [M + H +] 1 H-NMR (DMSO-d 6, 30 ° C): d ppm (Internal TMS standard): 1.70 - 1.83 (1H, m), 2.05 - 2.14 (1H, m) , 2.49 - 2.76 (4H, m), 3.84 (3H, s), 3.86 - 3.93 (1H, m), 6.61 (1H, d, J = 3.1 Hz), 7.43 (1H, s), 7.44 (1H, d , J = 3.1 Hz), 7.54 (1H, d, J = 8.9 Hz), 7.83 (1H, d, J = 8.9 Hz), 8.36 (1H, s).

Compound B: LC-ESI: 280 [M + H +] 1 H-NMR (DMSO-de, 30 ° C): d ppm (Internal TMS standard). 1.72 - 1.83 (1H, m), 2.05 - 2.12 (1H, m), 2.52 - 2.78 (4H, m), 3.89 (3H, s), 3.93 - 4.03 (1H, m), 6.52 (1H, d, J = 3.1 Hz), 7.43 (1H, s), 7.57 (1H, d, J = 3.1 Hz), 7.64 (1H, d, J = 8.2 Hz), 7.70 (1H, dd, J = 8.2 Hz, J = 1.2 Hz), 8.20 (1H, s).

Industrial Applicability According to the production method of the present invention as described above, the reaction progresses by maintaining the stenochemistry, so that the ramosetron or a salt thereof having a high optical purity with high acid yield can be produced (R ) -4,5,6,7-tetrahydro-1 H-benzimidazole-5-carboxylic acid or a salt thereof, which can be easily produced. In addition, the composition comprising the ramosetron or a salt thereof, obtained by the aforementioned production method, can be used as a therapeutic agent and / or preventive agent for digestive symptoms (nausea, emesis) caused by the administration of an agent malignant antitumor (cisplatin or similar), irritable bowel syndrome of diarrheal type, diarrheal symptoms of irritable bowel syndrome and the like.

Claims (8)

1. A method for producing the ramosetron or a salt thereof, characterized in that a compound represented by a formula (I) [the sign in the formula has the following meaning, X: a halogen] or a salt thereof, is allowed to react with 1-methyl-1 H-indole in the presence of a Lewis acid selected from the group consisting of a dihalide of lower alkylaluminum, a lower di-alkylaluminum halide, a lower tri-alkylaluminum and a lower alkylaluminum sesquihalide.

2. A method for producing the ramosetron or a salt thereof, characterized in that a compound represented by the formula (I) described according to claim 1, is prepared by leaving the acid (R) -4,5,6,7. -tetrahydro-1H-benzimidazole-5-carboxylic acid or a salt thereof reacting with a halogenation agent, and then allowed to react with 1-methyl-1 H-indole in the presence of a Lewis acid selected from the group consisting of a lower alkylaluminum dihalide, a lower di-alkylaluminum halide, a lower tri-alkylaluminium and a lower alkylaluminum sesquihalide.

3. The production method described according to claim 1 or 2, wherein the Lewis acid is ethylaluminum chloride or diethylaluminum sesquichloride.

4. The production method described according to claim 3, wherein the solvent of the reaction is an aromatic hydrocarbon.

5. The production method described according to claim 4, wherein the aromatic hydrocarbon is toluene.

6. Ramosetron or a salt thereof, produced by the production method described in accordance with claim 1.

7. Ramosetron or a salt thereof, produced by the production method described in accordance with claim 2.

8. A composition comprising ramosetron or a salt thereof, characterized in that it contains 5 - [(1-methyl-1 H -indol-5-yl) carbonyl] -4,5,6,7-tetrahydro-1 H-benzimidazole or a salt of the same and / or 5 - [(1-methyl-1H-indol-6-yl) carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole or a salt thereof, in a total amount of less than 1% based on the ramosetron or a salt thereof.