2-AMINO-1-MORPHOLIN-4-YL-ETHANONE HCL

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)-amide (75 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-amino-1-morpholino-1-ethanone hydrochloride (56 mg), HBTU (127 mg), and DIEA (73 uL). LC/MS: m/z 485.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.53 (t, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.40 (d, 1H), 4.16 (d, 2H), 3.64 (s, 3H), 3.63-3.60 (m, 2H), 3.58 (t, 2H), 3.55-3.50 (m, 2H), 3.50-3.45 (m, 2H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In N,N-dimethylformamide (100 ml), N-tert-butoxycarbonylglycine (2.00 g), morpholine (1.00 ml), 1-hydroxybenzotriazole monohydrate (1.74 g) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.84 g) were dissolved, followed by stirring overnight at room temperature. After concentration under reduced pressure, the residue was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=100:1), whereby a colorless foam was obtained. The substance was dissolved in dichloromethane (2 ml), followed by the addition of saturated solution of hydrochloride in ethanol (10 ml). The resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated to dryness under reduced pressure, whereby the title compound (1.80 g, quant.) was obtained as a pale yellow foam was obtained. After concentration under reduced pressure the residue was diluted with dichloromethane washed with water dried over anhydrous sodium sulfate The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=100:1), whereby a colorless foam was obtained The resulting mixture was stirred at room temperature for 5 minutes The reaction mixture was concentrated to dryness under reduced pressure, whereby the title compound (1.80 g, quant.) was obtained as a pale yellow foam was obtained

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: D 4-[2-(2-Fluorobenzylidaneamino)acetyl]morpholine can be prepared as described in Example 2D, but from 5.3 cm3 of 2-fluorobenzaldehyde, 9.1 g of 4-(2-aminoacetyl)morpholine hydrochloride, 6 g of 4 Å seive and 7 cm3 of triethylamine in 150 cm3 of dichloromethane. After treatment, there are obtained 12 g of 4-[2-(2-fluorobenzylideneamino)acetyl]morpholine in the form of an oil used as is in the subsequent syntheses.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: D 4-[2-(2-Fluorobenzylidaneamino)acetyl]morpholine can be prepared as described in Example 2D, but from 5.3 cm3 of 2-fluorobenzaldehyde, 9.1 g of 4-(2-aminoacetyl)morpholine hydrochloride, 6 g of 4 Å seive and 7 cm3 of triethylamine in 150 cm3 of dichloromethane. After treatment, there are obtained 12 g of 4-[2-(2-fluorobenzylideneamino)acetyl]morpholine in the form of an oil used as is in the subsequent syntheses.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)-amide (75 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-amino-1-morpholino-1-ethanone hydrochloride (56 mg), HBTU (127 mg), and DIEA (73 uL). LC/MS: m/z 485.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.53 (t, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.40 (d, 1H), 4.16 (d, 2H), 3.64 (s, 3H), 3.63-3.60 (m, 2H), 3.58 (t, 2H), 3.55-3.50 (m, 2H), 3.50-3.45 (m, 2H).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In N,N-dimethylformamide (100 ml), N-tert-butoxycarbonylglycine (2.00 g), morpholine (1.00 ml), 1-hydroxybenzotriazole monohydrate (1.74 g) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.84 g) were dissolved, followed by stirring overnight at room temperature. After concentration under reduced pressure, the residue was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=100:1), whereby a colorless foam was obtained. The substance was dissolved in dichloromethane (2 ml), followed by the addition of saturated solution of hydrochloride in ethanol (10 ml). The resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated to dryness under reduced pressure, whereby the title compound (1.80 g, quant.) was obtained as a pale yellow foam was obtained. After concentration under reduced pressure the residue was diluted with dichloromethane washed with water dried over anhydrous sodium sulfate The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=100:1), whereby a colorless foam was obtained The resulting mixture was stirred at room temperature for 5 minutes The reaction mixture was concentrated to dryness under reduced pressure, whereby the title compound (1.80 g, quant.) was obtained as a pale yellow foam was obtained

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In N,N-dimethylformamide (100 ml), N-tert-butoxycarbonylglycine (2.00 g), morpholine (1.00 ml), 1-hydroxybenzotriazole monohydrate (1.74 g) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.84 g) were dissolved, followed by stirring overnight at room temperature. After concentration under reduced pressure, the residue was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=100:1), whereby a colorless foam was obtained. The substance was dissolved in dichloromethane (2 ml), followed by the addition of saturated solution of hydrochloride in ethanol (10 ml). The resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated to dryness under reduced pressure, whereby the title compound (1.80 g, quant.) was obtained as a pale yellow foam was obtained. After concentration under reduced pressure the residue was diluted with dichloromethane washed with water dried over anhydrous sodium sulfate The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=100:1), whereby a colorless foam was obtained The resulting mixture was stirred at room temperature for 5 minutes The reaction mixture was concentrated to dryness under reduced pressure, whereby the title compound (1.80 g, quant.) was obtained as a pale yellow foam was obtained

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 67 mg of 1-hydroxybenzotriazole, 0.14 cm3 of triethylamine and 270 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added successively to a solution of 500 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)benzoic acid and 215 mg of 2-amino-1-morpholin-4-ylethanone hydrochloride in 15 cm3 of tetrahydrofuran. The reaction mixture is left stirring overnight at a temperature in the region of 20° C. After concentration of the reaction medium to dryness under reduced pressure, the residue obtained is taken up with dichloromethane. The organic phase is washed with water, dried, and concentrated to dryness under reduced pressure, to give a reaction crude which is purified by flash chromatography on a Merck 30 g silica cartridge (elution gradient: 100/0 to 95/5 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a white foam is obtained which crystallizes after trituration with diethyl ether. After filtration and drying using a vane pump, 470 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N-(2-morpholin-4-yl-2-oxoethyl)benzamide are thus obtained in the form of white crystals. The reaction mixture is left After concentration of the reaction medium to dryness under reduced pressure, the residue obtained The organic phase is washed with water dried concentrated to dryness under reduced pressure to give a reaction crude which is purified by flash chromatography on a Merck 30 g silica cartridge (elution gradient: 100/0 to 95/5 dichloromethane/methanol) After concentration of the fractions under reduced pressure, a white foam is obtained which crystallizes after trituration with diethyl ether After filtration drying are thus obtained in the form of white crystals

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of the above 2-amino-1-morpholin-4-yl-ethanone hydrochloride (0.23 g, 1.3 mmol) in methylene chloride (4.0 mL) and triethylamine (0.19 mL, 1.4 mmol), 4 angstrom sieves (10 beads, pulverized to a powder) were added, followed by trimethylacetaldehyde (0.35 mL, 3.3 mmol) at room temperature, under argon. The resulting mixture was stirred at room temperature overnight after which time sodium triacetoxyborohydride (0.54 g, 2.6 mmol) was added. After 6 h, the solids were removed via filtration and washed with methylene chloride. The combined filtrates were concentrated and the remaining residue was diluted with EtOAc and water. The aqueous phase was lyophilized to give a white solid that was diluted with EtOAc. The solids were removed via filtration and washed with EtOAc. The combined organics were concentrated to give the crude product which was purified via silica gel flash chromatography eluting with 100% EtOAc, then 0.5% NH4OH/10% MeOH/EtOAc, flow rate 30 mL/min. The product-containing fractions were concentrated to give 0.18 g (67%) of 2-(2,2-dimethyl-propylamino)-1-morpholin-4yl-ethanone. were added was added the solids were removed via filtration washed with methylene chloride The combined filtrates were concentrated the remaining residue was diluted with EtOAc and water to give a white solid The solids were removed via filtration washed with EtOAc The combined organics were concentrated to give the crude product which was purified via silica gel flash chromatography eluting with 100% EtOAc The product-containing fractions were concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of the above (2-morpholin-4-yl-2-oxo-ethyl)-carbamic acid tert-butyl ester (0.44 g, 1.8 mmol) in 1,4-dioxane (4.0 mL), HCl (4.0 mL of a 4 M solution in 1,4-dioxane) was added at room temperature. After one h, the precipitated product was collected via filtration and washed with EtOAc. The solid was dried under high vacuum to give 0.23 g (76%) of 2-amino-1-morpholin-4-yl-ethanone hydrochloride which was used without further purification. After one h, the precipitated product was collected via filtration washed with EtOAc The solid was dried under high vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: D 4-[2-(2-Fluorobenzylidaneamino)acetyl]morpholine can be prepared as described in Example 2D, but from 5.3 cm3 of 2-fluorobenzaldehyde, 9.1 g of 4-(2-aminoacetyl)morpholine hydrochloride, 6 g of 4 Å seive and 7 cm3 of triethylamine in 150 cm3 of dichloromethane. After treatment, there are obtained 12 g of 4-[2-(2-fluorobenzylideneamino)acetyl]morpholine in the form of an oil used as is in the subsequent syntheses.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)-amide (75 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-amino-1-morpholino-1-ethanone hydrochloride (56 mg), HBTU (127 mg), and DIEA (73 uL). LC/MS: m/z 485.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.53 (t, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.40 (d, 1H), 4.16 (d, 2H), 3.64 (s, 3H), 3.63-3.60 (m, 2H), 3.58 (t, 2H), 3.55-3.50 (m, 2H), 3.50-3.45 (m, 2H).