2-(2-methyl-1H-indol-3-yl)ethanamine

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of LiAlH4 (17 g, 445 mmol) in dry THF (1000 mL) is cooled to 0° C. and 2-methylindole-3-glyoxylamide (30 g, 148 mmol) is added in portions over 30 minutes. The mixture is stirred at room temperature for 30 minutes and then maintained at reflux for 3 hours. The reaction is cooled to 0° C. and treated with H2O (17 ml), 15% NaOH (aq., 17 ml) and H2O (51 ml). The mixture is treated with MgSO4, filtered and the filtrate evaporated to give 2-methyltryptamine which is dissolved in MeOH. Methyl 4-formylcinnamate (16.9 g, 88.8 mmol) is added to the solution, followed by NaBH3CN (8.4 g) and AcOH (1 equiv.). After 1 hour the reaction is diluted with NaHCO3 (aq.) and extracted with EtOAc. The organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by chromatography to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester. The ester is dissolved in MeOH, 1.0 M HCl/dioxane (1-1.5 equiv.) is added followed by Et2O. The resulting precipitate is filtered and the solid washed with Et2O and dried thoroughly to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to an ice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmol) and HONH2 (50% aq. solution, 24.0 mL, ca. 391.2 mmol). After 6 hours, the ice cold solution is diluted with H2O and NH4Cl (aq., 0.86 M, 100 mL). The resulting precipitate is filtered, washed with H2O and dried to afford N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (m/z 350 [MH+]). maintained at reflux for 3 hours The reaction is cooled to 0° C. filtered the filtrate evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of LiAlH4 (17 g, 445 mmol) in dry THF (1000 mL) is cooled to 0° C. and 2-methylindole-3-glyoxylamide (30 g, 148 mmol) is added in portions over 30 minutes. The mixture is stirred at room temperature for 30 minutes and then maintained at reflux for 3 hours. The reaction is cooled to 0° C. and treated with H2O (17 ml), 15% NaOH (aq., 17 ml) and H2O (51 ml). The mixture is treated with MgSO4, filtered and the filtrate evaporated to give 2-methyltryptamine which is dissolved in MeOH. Methyl 4-formylcinnamate (16.9 g, 88.8 mmol) is added to the solution, followed by NaBH3CN (8.4 g) and AcOH (1 equiv.). After 1 hour the reaction is diluted with NaHCO3 (aq.) and extracted with EtOAc. The organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by chromatography to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester. The ester is dissolved in MeOH, 1.0 M HCl/dioxane (1-1.5 equiv.) is added followed by Et2O. The resulting precipitate is filtered and the solid washed with Et2O and dried thoroughly to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to an ice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmol) and HONH2 (50% aq. solution, 24.0 mL, ca. 391.2 mmol). After 6 hours, the ice cold solution is diluted with H2O and NH4Cl (aq., 0.86 M, 100 mL). The resulting precipitate is filtered, washed with H2O and dried to afford N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (m/z 350 [MH+]). maintained at reflux for 3 hours The reaction is cooled to 0° C. filtered the filtrate evaporated

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyltryptamine (50 g, 287 mmole) and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester (54.6 g, 287 mmole) are suspended in methanol (514 g). The solution is stirred for 1 hour at 20-25° C., to allow the formation of the imine intermediate. The solution is cooled to −15° C. within ca. 20 minutes. Sodium borohydride (5.43 g, 143.5 mmole) is added in several portions during ca. 1 hour while maintaining the temperature at −15° C. to −10° C. The reaction mixture is stirred for additional 30 minutes at this temperature and the temperature is raised to 20-25° C. within ca. 25 minutes. The reaction mixture is stirred for 30 minutes at 20-25° C. and water (80 g) is slowly added while maintaining the temperature at 20-25° C. The pH of the reaction mixture is adjusted to 8.5 by slow addition of an aqueous hydrochloric acid solution (ca. 37.3 g of a 21.6 m/m % solution in water) at 20-25° C., until the pH of the solution reaches 8.5. The addition needs ca. 30 minutes in this case. After completion of the addition, the reaction mixture is stirred for one hour at 20-25° C. to allow crystallization. At this stage, the solution can be seeded with crystals of (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt to accelerate the crystallization. A suspension is obtained. A second portion of aqueous hydrochloric acid (36 g of a 21.6% m/m HCl solution in water) is added to the suspension during 30 minutes at 20-25° C., followed by the addition of a third portion of aqueous hydrochloric acid (167.7 g of a 21.6% m/m HCl solution in water) during 30 minutes at 20-25° C. The suspension is heated to 65° C. Then, the suspension is cooled to −15° C. and stirred for 30 minutes at −10 to −15° C. to complete the crystallization. The product is isolated by filtration and the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g). The wet product is dried at 50° C. under reduced pressure to obtain pure (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt as product. The product has usually >99 area % purity according to HPLC. IR, NMR and HR-MS confirmed the proposed structure. Melting point: decomposition starting at 251-252° C. The solution is cooled to −15° C. within ca. 20 minutes while maintaining the temperature at −15° C. to −10° C The reaction mixture is stirred for additional 30 minutes at this temperature the temperature is raised to 20-25° C. within ca. 25 minutes The reaction mixture is stirred for 30 minutes at 20-25° C. while maintaining the temperature at 20-25° C The addition needs ca. 30 minutes in this case After completion of the addition the reaction mixture is stirred for one hour at 20-25° C. crystallization the crystallization A suspension is obtained The suspension is heated to 65° C Then, the suspension is cooled to −15° C. stirred for 30 minutes at −10 to −15° C. the crystallization The product is isolated by filtration the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g) The wet product is dried at 50° C. under reduced pressure

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyltryptamine (50 g, 287 mmole) and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester (54.6 g, 287 mmole) are suspended in methanol (514 g). The solution is stirred for 1 hour at 20-25° C., to allow the formation of the imine intermediate. The solution is cooled to −15° C. within ca. 20 minutes. Sodium borohydride (5.43 g, 143.5 mmole) is added in several portions during ca. 1 hour while maintaining the temperature at −15° C. to −10° C. The reaction mixture is stirred for additional 30 minutes at this temperature and the temperature is raised to 20-25° C. within ca. 25 minutes. The reaction mixture is stirred for 30 minutes at 20-25° C. and water (80 g) is slowly added while maintaining the temperature at 20-25° C. An aqueous solution of hydrochloric acid (70.5 g concentrated HCl in 50 g of water) is slowly added to the reaction mixture such that the temperature is maintained at 20-25° C. and the hydrogen gas evolution can be controlled. The addition needs ca. 1 hour in this case. A second portion of aqueous hydrochloric acid solution (70.5 g concentrated HCl in 50 g water) is added within 30 minutes and the temperature is raised to 65° C. within 30 minutes. The suspension is stirred for 30 minutes at 65° C. and the temperature is lowered to −15° C. within 45 minutes. After 10 minutes stirring at −15° C., the temperature is raised again to 65° C. and the suspension is stirred for 30 minutes at this temperature. Finally, the suspension is cooled to −15° C. within 45 minutes and stirring is continued for additional 30 minutes at this temperature. The product is isolated by filtration and the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g). The wet product is dried at 50° C. under reduced pressure to obtain pure (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt as product. The product has usually >99 area % purity according to HPLC. IR, NMR and HR-MS confirmed the proposed structure. Melting point: decomposition starting at 251-252° C. The solution is cooled to −15° C. within ca. 20 minutes while maintaining the temperature at −15° C. to −10° C The reaction mixture is stirred for additional 30 minutes at this temperature the temperature is raised to 20-25° C. within ca. 25 minutes The reaction mixture is stirred for 30 minutes at 20-25° C. while maintaining the temperature at 20-25° C is maintained at 20-25° C. The addition needs ca. 1 hour in this case the temperature is raised to 65° C. within 30 minutes The suspension is stirred for 30 minutes at 65° C. the temperature is lowered to −15° C. within 45 minutes After 10 minutes stirring at −15° C. the temperature is raised again to 65° C. the suspension is stirred for 30 minutes at this temperature Finally, the suspension is cooled to −15° C. within 45 minutes stirring is continued for additional 30 minutes at this temperature The product is isolated by filtration the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g) The wet product is dried at 50° C. under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The third embodiment of the present invention is directed to a method of making a starting material useful in the synthesis of (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt. In particular, the third embodiment of the present invention is directed to a method of making 2-methyltryptamine comprising the steps of: (a) providing an admixture of phenylhydrazine and 5-chloro-2-pentanone in ethanol at a first temperature; (b) adding ethanol to the admixture and refluxing the mixture; (c) distilling ethanol; (d) adding water to the residual solution; (e) cooling the residual solution to form 2-methyltryptamine.

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyltryptamine (50 g, 287 mmole) and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester (54.6 g, 287 mmole) are suspended in methanol (514 g). The solution is stirred for 1 hour at 20-25° C., to allow the formation of the imine intermediate. The solution is cooled to −15° C. within ca. 20 minutes. Sodium borohydride (5.43 g, 143.5 mmole) is added in several portions during ca. 1 hour while maintaining the temperature at −15° C. to −10° C. The reaction mixture is stirred for additional 30 minutes at this temperature and the temperature is raised to 20-25° C. within ca. 25 minutes. The reaction mixture is stirred for 30 minutes at 20-25° C. and water (80 g) is slowly added while maintaining the temperature at 20-25° C. The pH of the reaction mixture is adjusted to 8.5 by slow addition of an aqueous hydrochloric acid solution (ca. 37.3 g of a 21.6 m/m % solution in water) at 20-25° C., until the pH of the solution reaches 8.5. The addition needs ca. 30 minutes in this case. After completion of the addition, the reaction mixture is stirred for one hour at 20-25° C. to allow crystallization. At this stage, the solution can be seeded with crystals of (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt to accelerate the crystallization. A suspension is obtained. A second portion of aqueous hydrochloric acid (36 g of a 21.6% m/m HCl solution in water) is added to the suspension during 30 minutes at 20-25° C., followed by the addition of a third portion of aqueous hydrochloric acid (167.7 g of a 21.6% m/m HCl solution in water) during 30 minutes at 20-25° C. The suspension is heated to 65° C. Then, the suspension is cooled to −15° C. and stirred for 30 minutes at −10 to −15° C. to complete the crystallization. The product is isolated by filtration and the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g). The wet product is dried at 50° C. under reduced pressure to obtain pure (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt as product. The product has usually >99 area % purity according to HPLC. IR, NMR and HR-MS confirmed the proposed structure. Melting point: decomposition starting at 251-252° C. The solution is cooled to −15° C. within ca. 20 minutes while maintaining the temperature at −15° C. to −10° C The reaction mixture is stirred for additional 30 minutes at this temperature the temperature is raised to 20-25° C. within ca. 25 minutes The reaction mixture is stirred for 30 minutes at 20-25° C. while maintaining the temperature at 20-25° C The addition needs ca. 30 minutes in this case After completion of the addition the reaction mixture is stirred for one hour at 20-25° C. crystallization the crystallization A suspension is obtained The suspension is heated to 65° C Then, the suspension is cooled to −15° C. stirred for 30 minutes at −10 to −15° C. the crystallization The product is isolated by filtration the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g) The wet product is dried at 50° C. under reduced pressure

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyltryptamine (50 g, 287 mmole) and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester (54.6 g, 287 mmole) are suspended in methanol (514 g). The solution is stirred for 1 hour at 20-25° C., to allow the formation of the imine intermediate. The solution is cooled to −15° C. within ca. 20 minutes. Sodium borohydride (5.43 g, 143.5 mmole) is added in several portions during ca. 1 hour while maintaining the temperature at −15° C. to −10° C. The reaction mixture is stirred for additional 30 minutes at this temperature and the temperature is raised to 20-25° C. within ca. 25 minutes. The reaction mixture is stirred for 30 minutes at 20-25° C. and water (80 g) is slowly added while maintaining the temperature at 20-25° C. An aqueous solution of hydrochloric acid (70.5 g concentrated HCl in 50 g of water) is slowly added to the reaction mixture such that the temperature is maintained at 20-25° C. and the hydrogen gas evolution can be controlled. The addition needs ca. 1 hour in this case. A second portion of aqueous hydrochloric acid solution (70.5 g concentrated HCl in 50 g water) is added within 30 minutes and the temperature is raised to 65° C. within 30 minutes. The suspension is stirred for 30 minutes at 65° C. and the temperature is lowered to −15° C. within 45 minutes. After 10 minutes stirring at −15° C., the temperature is raised again to 65° C. and the suspension is stirred for 30 minutes at this temperature. Finally, the suspension is cooled to −15° C. within 45 minutes and stirring is continued for additional 30 minutes at this temperature. The product is isolated by filtration and the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g). The wet product is dried at 50° C. under reduced pressure to obtain pure (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt as product. The product has usually >99 area % purity according to HPLC. IR, NMR and HR-MS confirmed the proposed structure. Melting point: decomposition starting at 251-252° C. The solution is cooled to −15° C. within ca. 20 minutes while maintaining the temperature at −15° C. to −10° C The reaction mixture is stirred for additional 30 minutes at this temperature the temperature is raised to 20-25° C. within ca. 25 minutes The reaction mixture is stirred for 30 minutes at 20-25° C. while maintaining the temperature at 20-25° C is maintained at 20-25° C. The addition needs ca. 1 hour in this case the temperature is raised to 65° C. within 30 minutes The suspension is stirred for 30 minutes at 65° C. the temperature is lowered to −15° C. within 45 minutes After 10 minutes stirring at −15° C. the temperature is raised again to 65° C. the suspension is stirred for 30 minutes at this temperature Finally, the suspension is cooled to −15° C. within 45 minutes stirring is continued for additional 30 minutes at this temperature The product is isolated by filtration the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g) The wet product is dried at 50° C. under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The third embodiment of the present invention is directed to a method of making a starting material useful in the synthesis of (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt. In particular, the third embodiment of the present invention is directed to a method of making 2-methyltryptamine comprising the steps of: (a) providing an admixture of phenylhydrazine and 5-chloro-2-pentanone in ethanol at a first temperature; (b) adding ethanol to the admixture and refluxing the mixture; (c) distilling ethanol; (d) adding water to the residual solution; (e) cooling the residual solution to form 2-methyltryptamine.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of LiAlH4 (17 g, 445 mmol) in dry THF(1000 mL) is cooled to 0° C. and 2-methylindole-3-glyoxylamide (30 g, 148 mmol) is added in portions over 30 min. The mixture is stirred at room temperature for 30 min. and then maintained at reflux for 3 h. The reaction is cooled to 0° C. and treated with H2O (17 ml), 15% NaOH (aq., 17 ml) and H2O (51 ml). The mixture with MgSO4, filtered and the filtrate evaporated to give 2-methyltryptamine which is dissolved in MeOH. Methyl 4-formylcinnamate (16.9 g, 88.8 mmol) is added to the solution, followed by NaBH3CN (8.4 g) and AcOH (1 equiv.). After 1 h the reaction is diluted with NaHCO3 (aq.) and extracted with EtOAc. The organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by chromatography to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester. The ester is dissolved in MeOH, 1.0 M HCl/dioxane (1-1.5 eqiv.) is added followed by Et2O. The resulting precipitate is filtered and the solid washed with Et2O and dried thoroughly to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to an ice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmol) and HONH2 (50% aq. solution, 24.0 mL, ca. 391.2 mmol). After 6 h, the ice cold solution is diluted with H2O and NH4Cl (aq., 0.86 M, 100 mL). The resulting precipitate is filtered, washed with H2O and dried to afford N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (m/z 350 [MH+]). maintained at reflux for 3 h The reaction is cooled to 0° C. The mixture with MgSO4, filtered the filtrate evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of LiAlH4 (17 g, 445 mmol) in dry THF(1000 mL) is cooled to 0° C. and 2-methylindole-3-glyoxylamide (30 g, 148 mmol) is added in portions over 30 min. The mixture is stirred at room temperature for 30 min. and then maintained at reflux for 3 h. The reaction is cooled to 0° C. and treated with H2O (17 ml), 15% NaOH (aq., 17 ml) and H2O (51 ml). The mixture with MgSO4, filtered and the filtrate evaporated to give 2-methyltryptamine which is dissolved in MeOH. Methyl 4-formylcinnamate (16.9 g, 88.8 mmol) is added to the solution, followed by NaBH3CN (8.4 g) and AcOH (1 equiv.). After 1 h the reaction is diluted with NaHCO3 (aq.) and extracted with EtOAc. The organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by chromatography to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester. The ester is dissolved in MeOH, 1.0 M HCl/dioxane (1-1.5 eqiv.) is added followed by Et2O. The resulting precipitate is filtered and the solid washed with Et2O and dried thoroughly to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to an ice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmol) and HONH2 (50% aq. solution, 24.0 mL, ca. 391.2 mmol). After 6 h, the ice cold solution is diluted with H2O and NH4Cl (aq., 0.86 M, 100 mL). The resulting precipitate is filtered, washed with H2O and dried to afford N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (m/z 350 [MH+]). maintained at reflux for 3 h The reaction is cooled to 0° C. The mixture with MgSO4, filtered the filtrate evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of LiAlH4 (17 g, 445 mmol) in dry THF(1000 mL) is cooled to 0° C. and 2-methylindole-3-glyoxylamide (30 g, 148 mmol) is added in portions over 30 min. The mixture is stirred at room temperature for 30 min. and then maintained at reflux for 3 h. The reaction is cooled to 0° C. and treated with H2O (17 ml), 15% NaOH (aq., 17 ml) and H2O (51 ml). The mixture with MgSO4, filtered and the filtrate evaporated to give 2-methyltryptamine which is dissolved in MeOH. Methyl 4-formylcinnamate (16.9 g, 88.8 mmol) is added to the solution, followed by NaBH3CN (8.4 g) and AcOH (1 equiv.). After 1 h the reaction is diluted with NaHCO3 (aq.) and extracted with EtOAc. The organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by chromatography to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester. The ester is dissolved in MeOH, 1.0 M HCl/dioxane (1-1.5 eqiv.) is added followed by Et2O. The resulting precipitate is filtered and the solid washed with Et2O and dried thoroughly to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to an ice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmol) and HONH2 (50% aq. solution, 24.0 mL, ca. 391.2 mmol). After 6 h, the ice cold solution is diluted with H2O and NH4Cl (aq., 0.86 M, 100 mL). The resulting precipitate is filtered, washed with H2O and dried to afford N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (m/z 350 [MH+]). maintained at reflux for 3 h The reaction is cooled to 0° C. The mixture with MgSO4, filtered the filtrate evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-2-(1H-Indol-3-yl)-1-methylethylamine (0.43 g, 2.5 mmol) and di-t-butyl dicarbonate (0.60 g, 2.75 mmol) in acetone is treated dropwise with aqueous K2CO3 (3.5 g, 25 mmol) at 0° C., allowed to warm to room temperature for 16 h, concentrated to an aqueous residue and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo to dryness. This residue is chromatographed (silica gel, 10%-50% EtOAc in hexanes as gradient eluent) to give the protected®-2-methyl tryptamine. A mixture of the protected tryptamine (0.17 g, 0.62 mmol) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (0.16 g, 0.62 mmol) in THF is treated with potassium t-butoxide (77 mg, 0.68 mmol) at room temperature, stirred for 1 H, poured into saturated NaHCO3 and extracted with EtOAc. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The resultant residue is dispersed in THF and 4N HCl in dioxane, stirred for 16 h, concentrated in vacuo and purified by HPLC1 to afford the title product as a beige solid, 0.62 mg (35% yield), identified by NMR and mass spectral analyses. extracted with EtOAc dried over Na2SO4 concentrated in vacuo The resultant residue is dispersed in THF 4N HCl in dioxane, stirred for 16 h concentrated in vacuo purified by HPLC1