2-(2-methoxyethoxy)ethanamine

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-methoxy-ethoxy)-ethyl]-amide (44 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-(2-methoxy-ethoxy)-ethylamine (24 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 511.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.50 (t, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.74 (d, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 3.64 (s, 3H), 3.59-3.53 (m, 4H), 3.49-3.41 (m, 4H), 3.25 (s, 3H).

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

Procedure: A suspension of carbaldehyde 325 (0.50 g, 1.3 mmol), amine 326 (0.30 g, 2.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in dichloromethane (20 ml) was stirred for 1 h at room temperature. Then sodium triacetoxyborohydride (0.80 g, 3.8 mmol) was added and stirred at r.t. for 16 h. A further amount of sodium triacetoxyborohydride (1.0 g) was then added, and stirring continued for 2 h. The reaction mixture was partitioned between dichloromethane and 1N NaOH. The yellow suspension was removed by filtration and rinsed with dichloromethane and 1N NaOH. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 100 g column) to yield 327 (280 mg, 0.562 mmol, 44%) as a yellow solid. LRMS (M+H): 499.4 stirred at r.t. for 16 h stirring continued for 2 h The reaction mixture was partitioned between dichloromethane and 1N NaOH The yellow suspension was removed by filtration rinsed with dichloromethane and 1N NaOH The organic extract was dried over anhydrous sodium sulfate filtered concentrated The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 100 g column)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 2-(2-methoxyethoxyl)ethanamine (0.820 g, 6.88 mmol) in DMF (69 mL) at 0° C. was added dropwise a solution of 1,1′-thiocarbonyldiimidazole (1.349 g, 7.57 mmol) in 21 mL of DMF. The mixture was warmed to RT and stirred for 90 min. The mixture was poured into water (130 mL) and extracted with Et2O (70 mL). The Et2O layer was washed with water, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo (325 torr, bath temp: 24° C.) to afford 1-isothiocyanato-2-(2-methoxyethoxyl)ethane (0.678 g, 4.21 mmol, 61% yield) as a yellow oil. The crude material was used in next step. extracted with Et2O (70 mL) The Et2O layer was washed with water dried over Na2SO4 filtered The filtrate was concentrated in vacuo (325 torr, bath temp: 24° C.)

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

Procedure: A suspension of carbaldehyde 325 (0.50 g, 1.3 mmol), amine 326 (0.30 g, 2.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in dichloromethane (20 ml) was stirred for 1 h at room temperature. Then sodium triacetoxyborohydride (0.80 g, 3.8 mmol) was added and stirred at r.t. for 16 h. A further amount of sodium triacetoxyborohydride (1.0 g) was then added, and stirring continued for 2 h. The reaction mixture was partitioned between dichloromethane and 1N NaOH. The yellow suspension was removed by filtration and rinsed with dichloromethane and 1N NaOH. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 100 g column) to yield 327 (280 mg, 0.562 mmol, 44%) as a yellow solid. LRMS (M+H): 499.4 stirred at r.t. for 16 h stirring continued for 2 h The reaction mixture was partitioned between dichloromethane and 1N NaOH The yellow suspension was removed by filtration rinsed with dichloromethane and 1N NaOH The organic extract was dried over anhydrous sodium sulfate filtered concentrated The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 100 g column)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.96 g (50.0 mmol) of 2-(2-methoxyethoxy)ethylamine and 3.00 g (50.0 mmol) of acetic acid were placed in a 30 ml two neck flask. While heating the flask in a 90° C. oil bath, 3.10 g (73.7 mmol) of cyanamide was added. After 5 hours of the reaction, the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid) to obtain 3.15 g of the title compound (wax-like, 14.2 mmol, 28.5% in yield) in the form of acetate. Results of the analysis of this compound are as follows. After 5 hours of the reaction the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.96 g (50.0 mmol) of 2-(2-methoxyethoxy)ethylamine and 3.00 g (50.0 mmol) of acetic acid were placed in a 30 ml two neck flask. While heating the flask in a 90° C. oil bath, 3.10 g (73.7 mmol) of cyanamide was added. After 5 hours of the reaction, the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid) to obtain 3.15 g of the title compound (wax-like, 14.2 mmol, 28.5% in yield) in the form of acetate. Results of the analysis of this compound are as follows. After 5 hours of the reaction the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid)

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

Procedure: 1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-methoxy-ethoxy)-ethyl]-amide (44 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-(2-methoxy-ethoxy)-ethylamine (24 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 511.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.50 (t, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.74 (d, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 3.64 (s, 3H), 3.59-3.53 (m, 4H), 3.49-3.41 (m, 4H), 3.25 (s, 3H).

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

Procedure: A suspension of carbaldehyde 325 (0.50 g, 1.3 mmol), amine 326 (0.30 g, 2.5 mmol) and acetic acid (0.14 ml, 2.5 mmol) in dichloromethane (20 ml) was stirred for 1 h at room temperature. Then sodium triacetoxyborohydride (0.80 g, 3.8 mmol) was added and stirred at r.t. for 16 h. A further amount of sodium triacetoxyborohydride (1.0 g) was then added, and stirring continued for 2 h. The reaction mixture was partitioned between dichloromethane and 1N NaOH. The yellow suspension was removed by filtration and rinsed with dichloromethane and 1N NaOH. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 100 g column) to yield 327 (280 mg, 0.562 mmol, 44%) as a yellow solid. LRMS (M+H): 499.4 stirred at r.t. for 16 h stirring continued for 2 h The reaction mixture was partitioned between dichloromethane and 1N NaOH The yellow suspension was removed by filtration rinsed with dichloromethane and 1N NaOH The organic extract was dried over anhydrous sodium sulfate filtered concentrated The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 100 g column)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.96 g (50.0 mmol) of 2-(2-methoxyethoxy)ethylamine and 3.00 g (50.0 mmol) of acetic acid were placed in a 30 ml two neck flask. While heating the flask in a 90° C. oil bath, 3.10 g (73.7 mmol) of cyanamide was added. After 5 hours of the reaction, the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid) to obtain 3.15 g of the title compound (wax-like, 14.2 mmol, 28.5% in yield) in the form of acetate. Results of the analysis of this compound are as follows. After 5 hours of the reaction the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.96 g (50.0 mmol) of 2-(2-methoxyethoxy)ethylamine and 3.00 g (50.0 mmol) of acetic acid were placed in a 30 ml two neck flask. While heating the flask in a 90° C. oil bath, 3.10 g (73.7 mmol) of cyanamide was added. After 5 hours of the reaction, the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid) to obtain 3.15 g of the title compound (wax-like, 14.2 mmol, 28.5% in yield) in the form of acetate. Results of the analysis of this compound are as follows. After 5 hours of the reaction the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=2/1 containing 0.5% acetic acid)