3-methylazetidine;hydrochloride

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

Procedure: Isopropyl acetate (300 mL) was charged into a 1000 ml 3-neck flask and cooled to −10˜−5° C. Sulfurisocyanatidic chloride (44.5 mL) was added at −5˜10° C. followed by the addition of phenylmethanol (50.5 mL) in isopropyl acetate (60 mL) at −5˜10° C. over 60 minutes. The mixture reacted at −5˜10° C. and was monitored by HPLC until the content of benzyl alcohol was <2% (after 1 hour at 0° C.). A mixture of acetonitrile (300 mL), 3-methylazetidine hydrochloride (50 g) (Intermediate C, either commercially available or prepared as set out below) and triethylamine (162 mL) was stirred in a 2000 mL 3-neck flask and to this was added the solution of the intermediate benzyl chlorosulfonylcarbamate in isopropyl acetate (360 mL) dropwise at <−5° C. over 90 minutes. The mixture was allowed to warm to RT overnight. The reaction was quenched with acetic acid and pH was adjusted to 4-5. The mixture was separated and the aqueous phase was washed with isopropyl acetate (500 ml) and then separated. The organic phase was combined and washed with 10% brine (2×120 ml), dried with anhydrous magnesium sulphate, filtered and the filter cake washed with isopropyl acetate (30 ml) and filtered to afford the sub-title product (145 g) as a red oil. cooled to −10˜−5° C The mixture reacted at −5˜10° C. <2% (after 1 hour at 0° C.) commercially available or prepared The reaction was quenched with acetic acid and pH The mixture was separated the aqueous phase was washed with isopropyl acetate (500 ml) separated washed with 10% brine (2×120 ml) dried with anhydrous magnesium sulphate filtered the filter cake washed with isopropyl acetate (30 ml) filtered

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

Procedure: 43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 12A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 25 mg (25% of theory) reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1.5 h The reaction mixture is concentrated under reduced pressure taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient)

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

Procedure: 43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 13A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 30 mg (30% of theory) reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h The reaction mixture is concentrated under reduced pressure taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient)

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

Procedure: 43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 13A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 30 mg (30% of theory) reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h The reaction mixture is concentrated under reduced pressure taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient)

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

Procedure: 43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 12A and 174 ml (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 25 mg (25% of theory) reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1.5 h The reaction mixture is concentrated under reduced pressure taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient)

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

Procedure: 43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 13A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 30 mg (30% of theory) reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h The reaction mixture is concentrated under reduced pressure taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient)

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

Procedure: 95 mg (0.19 mmol) of the compound from Example 184A and 61 mg (0.57 mmol) of 3-methylazetidine hydrochloride were reacted according to the General Method 6. Work-up of the crude product was carried out initially by column chromatography on silica gel (mobile phase: dichloromethane->dichloromethane/methanol 100:5) and additionally by preparative HPLC. Yield: 14 mg (17% of theory)

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

Procedure: Isopropyl acetate (300 mL) was charged into a 1000 ml 3-neck flask and cooled to −10˜−5° C. Sulfurisocyanatidic chloride (44.5 mL) was added at −5˜10° C. followed by the addition of phenylmethanol (50.5 mL) in isopropyl acetate (60 mL) at −5˜10° C. over 60 minutes. The mixture reacted at −5˜10° C. and was monitored by HPLC until the content of benzyl alcohol was <2% (after 1 hour at 0° C.). A mixture of acetonitrile (300 mL), 3-methylazetidine hydrochloride (50 g) (Intermediate C, either commercially available or prepared as set out below) and triethylamine (162 mL) was stirred in a 2000 mL 3-neck flask and to this was added the solution of the intermediate benzyl chlorosulfonylcarbamate in isopropyl acetate (360 mL) dropwise at <−5° C. over 90 minutes. The mixture was allowed to warm to RT overnight. The reaction was quenched with acetic acid and pH was adjusted to 4˜5. The mixture was separated and the aqueous phase was washed with isopropyl acetate (500 ml) and then separated. The organic phase was combined and washed with 10% brine (2×120 ml), dried with anhydrous magnesium sulphate, filtered and the filter cake washed with isopropyl acetate (30 ml) and filtered to afford the sub-title product (145 g) as a red oil. cooled to −10˜−5° C The mixture reacted at −5˜10° C. <2% (after 1 hour at 0° C.) commercially available or prepared The reaction was quenched with acetic acid and pH The mixture was separated the aqueous phase was washed with isopropyl acetate (500 ml) separated washed with 10% brine (2×120 ml) dried with anhydrous magnesium sulphate filtered the filter cake washed with isopropyl acetate (30 ml) filtered

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

Procedure: Isopropyl acetate (300 mL) was charged into a 1000 ml 3-neck flask and cooled to −10˜−5° C. Sulfurisocyanatidic chloride (44.5 mL) was added at −5˜10° C. followed by the addition of phenylmethanol (50.5 mL) in isopropyl acetate (60 mL) at −5˜10° C. over 60 minutes. The mixture reacted at −5˜10° C. and was monitored by HPLC until the content of benzyl alcohol was <2% (after 1 hour at 0° C.). A mixture of acetonitrile (300 mL), 3-methylazetidine hydrochloride (50 g) (Intermediate C, either commercially available or prepared as set out below) and triethylamine (162 mL) was stirred in a 2000 mL 3-neck flask and to this was added the solution of the intermediate benzyl chlorosulfonylcarbamate in isopropyl acetate (360 mL) dropwise at <−5° C. over 90 minutes. The mixture was allowed to warm to RT overnight. The reaction was quenched with acetic acid and pH was adjusted to 4-5. The mixture was separated and the aqueous phase was washed with isopropyl acetate (500 ml) and then separated. The organic phase was combined and washed with 10% brine (2×120 ml), dried with anhydrous magnesium sulphate, filtered and the filter cake washed with isopropyl acetate (30 ml) and filtered to afford the sub-title product (145 g) as a red oil. cooled to −10˜−5° C The mixture reacted at −5˜10° C. <2% (after 1 hour at 0° C.) commercially available or prepared The reaction was quenched with acetic acid and pH The mixture was separated the aqueous phase was washed with isopropyl acetate (500 ml) separated washed with 10% brine (2×120 ml) dried with anhydrous magnesium sulphate filtered the filter cake washed with isopropyl acetate (30 ml) filtered

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

Procedure: 43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 12A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 25 mg (25% of theory) reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 1.5 h The reaction mixture is concentrated under reduced pressure taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient)

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

Procedure: 43 mg (0.4 mmol) of 3-methylazetidine hydrochloride, 100 mg (0.3 mmol) of the compound from Example 13A and 174 μl (130 mg, 1.0 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are suspended in 2 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h. The reaction mixture is concentrated under reduced pressure, taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 30 mg (30% of theory) reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 4.5 h The reaction mixture is concentrated under reduced pressure taken up in water with addition of aqueous 1 N sodium hydroxide solution (pH=9-10) purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient)