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WO2005037823A1 - Procede de preparation de 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazole-1-yl)methyl]-4h-carbazol-4-one ou d'un sel de celui-ci - Google Patents

Procede de preparation de 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazole-1-yl)methyl]-4h-carbazol-4-one ou d'un sel de celui-ci Download PDF

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Publication number
WO2005037823A1
WO2005037823A1 PCT/KR2004/002647 KR2004002647W WO2005037823A1 WO 2005037823 A1 WO2005037823 A1 WO 2005037823A1 KR 2004002647 W KR2004002647 W KR 2004002647W WO 2005037823 A1 WO2005037823 A1 WO 2005037823A1
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compound
formula
amount
methyl
group
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English (en)
Inventor
Tai Au Lee
Sang Sun Park
Doo Byung Lee
Sang Jung Kim
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Yuhan Corp
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Yuhan Corp
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Priority claimed from KR1020030072099A external-priority patent/KR100566319B1/ko
Priority claimed from KR1020030072098A external-priority patent/KR100566318B1/ko
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Publication of WO2005037823A1 publication Critical patent/WO2005037823A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a process for preparing 1,2,3,9-tetrahydro- 9-methyl-3-[(2-methyl-lH-imidazole-l-yl)methyl]-4H-carbazol-4-one or its salt, which is used as an anti-vomiting agent.
  • 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 :
  • reaction scheme 4 The process disclosed in KR Pat. No. 0217466 may be summarized as following reaction scheme 4:
  • 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.
  • the reaction described in KR Pat. No. 0217466 is 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.
  • the present invention provides an improved process for preparing 1,2,3,9- tetrahydro-9-methyl-3-[(2-methyl-lH-imidazole-l-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.
  • 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:
  • R 1 , R 2 , R 3 and R 4 are each independently a C 1-6 alkyl or phenyl group, -(CH 2 ) m ring or -(CH 2 ) a -X-(CH 2 ) b ring, wherein m, a and b are each independently 1 to 5;
  • X is N, O or S, and if n is 1, R , R and R are each independently a C ⁇ -6 alkyl or aryl group; and R and R are each independently - CH 2 - group, and R , R and R are each independently a C 1-6 alkyl or aryl group.
  • 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:
  • 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 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.
  • 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 preferably 0.5 ⁇ 5 eq., based on the amount of the compound of formula 4.
  • 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.
  • the solvent may be selected from the group consisting of acetonitrile, ethylacetate, tetrahydrofuran, toluene, 1,4-dioxane, dimethylformamide and a mixture thereof.
  • 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.
  • 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 ⁇ , ⁇ -unsaturated ketone, the reactivity between the reaction materials is low, which makes it long-reaction time and low- yield.
  • the clay has many advantages of high-stability, low-price, recycle-potentiality, no 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.
  • Montmorillonite KSF or Montmorillonite K10 products of Aldrich
  • 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.
  • 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.
  • 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 compound of formula 6 is preferably in the range of about 1 - 10 eq., more preferably about 1.5 - 6 eq., based on the amount of the compound of formula 2.
  • the halide compound as a catalyst may be preferably a quaternary ammonium halide, representative examples thereof including, not limited to, tetrabutyl ammonium 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.
  • 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 -methyl enebis(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 l,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 HC1, 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-l ,3,5-rriazine 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 l,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 HC1, 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%).
  • Example 8 5 g of l,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 l,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 l,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 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 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 l,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one prepared in any one of Examples 1 to 7 and l lg of 2-methyl- 1 -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 l,2,3,9-tetrahydro-9-methyl-3-methylene-4H- carbazol-4-one prepared in any one of Examples 1 to 7 and l l 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 l,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-butyl ammonium 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 l,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 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 l,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 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 l,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%).
  • Example 22 5 g of l,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-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 cone. HC1 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.
  • Example 23 6 g of l,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-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 cone. HC1 was slowly added to the suspension, which was then stirred at room temperature for 30min.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé amélioré de préparation de 1,2,3,9-tétrahydro-9-méthyl-3-[(2-méthyl-1H-imidazol-1-yl)méthyl]-4H-carbazol-4-one ou d'un sel de celui-ci, utile en tant qu'agent anti-émétique, à haut rendement dans des conditions douces, afin d'être appliqué de manière avantageuse à une production de masse à grande échelle dudit composés.
PCT/KR2004/002647 2003-10-16 2004-10-15 Procede de preparation de 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazole-1-yl)methyl]-4h-carbazol-4-one ou d'un sel de celui-ci Ceased WO2005037823A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR1020030072099A KR100566319B1 (ko) 2003-10-16 2003-10-16 카바졸온 유도체의 제조방법
KR1020030072098A KR100566318B1 (ko) 2003-10-16 2003-10-16 카바졸온 유도체 제조 방법
KR10-2003-0072099 2003-10-16
KR10-2003-0072098 2003-10-16

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7696356B2 (en) * 2004-08-17 2010-04-13 Taro Pharmaceutical Industries Limited Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one and ondansetron therefrom
US11124503B2 (en) 2016-03-11 2021-09-21 California Institute Of Technology Compositions and methods for acylating lactams
US11214568B2 (en) 2018-10-18 2022-01-04 California Institute Of Technology Gem-disubstituted pyrrolidines, piperazines, and diazepanes, and compositions and methods of making the same
US11377396B2 (en) 2014-12-18 2022-07-05 California Institute Of Technology Enantioselective synthesis of α-quaternary Mannich adducts by palladium-catalyzed allylic alkylation
US11390585B2 (en) 2011-06-24 2022-07-19 California Institute Of Technology Quaternary heteroatom containing compounds

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US6388091B1 (en) * 2000-11-20 2002-05-14 Hanmi Pharm. Co., Ltd. Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3-{(2-methyl-1H-imidazol-1-yl)methyl}-4H-carbazol-4-one
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US6388091B1 (en) * 2000-11-20 2002-05-14 Hanmi Pharm. Co., Ltd. Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3-{(2-methyl-1H-imidazol-1-yl)methyl}-4H-carbazol-4-one
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7696356B2 (en) * 2004-08-17 2010-04-13 Taro Pharmaceutical Industries Limited Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one and ondansetron therefrom
US11390585B2 (en) 2011-06-24 2022-07-19 California Institute Of Technology Quaternary heteroatom containing compounds
US11377396B2 (en) 2014-12-18 2022-07-05 California Institute Of Technology Enantioselective synthesis of α-quaternary Mannich adducts by palladium-catalyzed allylic alkylation
US11124503B2 (en) 2016-03-11 2021-09-21 California Institute Of Technology Compositions and methods for acylating lactams
US11214568B2 (en) 2018-10-18 2022-01-04 California Institute Of Technology Gem-disubstituted pyrrolidines, piperazines, and diazepanes, and compositions and methods of making the same

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