2-methylsulfonylethyl methanesulfonate

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine (1.51 g, 2.44 mmol) and tetrahydrofuran (20 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of s-butyl lithium (3.94 mL, 1.3 M in hexane, 5.12 mmol). After 30 minutes, add a solution of 2-methylsulfonylethyl methanesulfonate (0.60 g, 2.93 mmol). Allow to warm to ambient temperature and then heat to reflux. After 48 hours, cool to ambient temperature and add water. Separate the layers. Extract the aqueous layer four times with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5/0.5/94.5 methanol/concentrated ammonium hydroxide/dichloromethane to give the title compound: Rf=0.54 (silica gel, 5/0.5/94.5 methanol/concentrated ammonium hydroxide/dichloromethane). Allow to warm to ambient temperature heat to reflux After 48 hours cool to ambient temperature Separate the layers Extract the aqueous layer four times with ethyl acetate dry over Na2SO4 filter evaporate in vacuo to give a residue

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

Procedure: To a solution of methanesulfonyl chloride (484 mg, 4.23 mmol) in 15 mL of DCM at 0° C. was added 2-methanesulfonyl-ethanol (500 mg, 4.03 mmol) in 10 mL of DCM followed by DIEA (1.05 mL, 6.05 mmol) under Ar. The mixture was warmed to RT and stirred for 20 h under Ar. The mixture was treated with 100 mL of EtOAc and washed with H2O (3×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent in vacuo gave 534 mg (66%) of the title compound as a brown oil. 1H-NMR (CDCl3; 400 MHz): δ 4.67 (d, 2H, J=5.5 Hz), 3.46 (d, 2H, J=5.5 Hz), 3.11 (s, 3H), 3.04 (s, 3H). washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) Removal of the solvent in vacuo

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

Procedure: To a solution of methanesulfonyl chloride (484 mg, 4.23 mmol) in 15 mL of DCM at 0° C. was added 2-methanesulfonyl-ethanol (500 mg, 4.03 mmol) in 10 mL of DCM followed by DIEA (1.05 mL, 6.05 mmol) under Ar. The mixture was warmed to RT and stirred for 20 h under Ar. The mixture was treated with 100 mL of EtOAc and washed with H2O (3×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent in vacuo gave 534 mg (66%) of the title compound as a brown oil. 1H-NMR (CDCl3; 400 MHz): δ 4.67 (d, 2H, J=5.5 Hz), 3.46 (d, 2H, J=5.5 Hz), 3.11 (s, 3H), 3.04 (s, 3H). washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) Removal of the solvent in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.05 g, 0.09 mmol) and tetrahydrofuran (5 mL). Cool to −78° C. using a dry-ice/acetone bath. Add dropwise a solution of sec-butyllithium (0.15 mL, 1.3 M, 0.19 mmol). When the addition of sec-butyllithium is complete, add a solution 2-methylsulfonylethyl mesylate (0.02 g, 0.10 mmol) in tetrahydrofuran (2 mL). Heat the reaction mixture to reflux. After 12 hours, cool, add sec-butyllithium (0.10 mL) and 2-methylsulfonylethyl mesylate (0.02 g, 0.10 mmol) and again heat the reaction mixture to reflux. After 12 hours, cool, add water, separate the layers and extract the aqueous layer twice with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 0.5% concentrated aqueous ammonia solution/5% methanol/dichloromethane to give the title compound: Rf=0.38 (silica gel, 0.5% concentrated aqueous ammonia solution/5% methanol/dichloromethane). Heat the reaction mixture to reflux cool again heat the reaction mixture to reflux After 12 hours cool separate the layers extract the aqueous layer twice with ethyl acetate dry over Na2SO4 filter evaporate in vacuo to give a residue

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

Procedure: Combine 2-methylsulfonylethanol (7.7 g, 62 mmol) and dichloromethane (50 mL). Cool in an ice bath. Add methanesulfonyl chloride (7.81 g , 68.2 mmol). Add N,N-diisopropylethylamine (8.0 g, 62 mmol). After the addition of N,N-diisopropylethylamine, warm to ambient temperature. After 12 hours, add water and separate the layers. Extract the organic layer and extract with a saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter and evaporate in vacuo to give the title compound: mp; 55-57° C. Cool in an ice bath separate the layers Extract the organic layer extract with a saturated aqueous sodium bicarbonate solution Dry the organic layer over Na2SO4 filter evaporate in vacuo

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

Procedure: Combine 2-methylsulfonylethanol (7.7 g, 62 mmol) and dichloromethane (50 mL). Cool in an ice bath. Add methanesulfonyl chloride (7.81 g , 68.2 mmol). Add N,N-diisopropylethylamine (8.0 g, 62 mmol). After the addition of N,N-diisopropylethylamine, warm to ambient temperature. After 12 hours, add water and separate the layers. Extract the organic layer and extract with a saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter and evaporate in vacuo to give the title compound: mp; 55-57° C. Cool in an ice bath separate the layers Extract the organic layer extract with a saturated aqueous sodium bicarbonate solution Dry the organic layer over Na2SO4 filter evaporate in vacuo

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

Procedure: In a 100 mL round-bottomed flask, (S)-2-(benzyloxycarbonylamino)propanoic acid (331 mg, 1.48 mmol, Eq: 1.00) was combined with THF (9 mL) to give a colorless solution. Sodium hydride (131 mg, 3.26 mmol, Eq: 2.2) was added. The reaction was stirred at rt for 30 min, then 2-(methylsulfonyl)ethyl methanesulfonate (300 mg, 1.48 mmol, Eq: 1.00) was added and the reaction was stirred at rt overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% EtOAc in hexanes) to give (S)-2-[benzyloxycarbonyl-(2-methanesulfonyl-ethyl)-amino]-propionic acid (201 mg). to give a colorless solution the reaction was stirred at rt overnight The reaction was quenched with saturated aqueous NH4Cl extracted with EtOAc The combined organic layers were washed with water and brine then dried over Na2SO4 concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% EtOAc in hexanes)

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

Procedure: In a 100 mL round-bottomed flask, (S)-2-(benzyloxycarbonylamino)propanoic acid (331 mg, 1.48 mmol, Eq: 1.00) was combined with THF (9 mL) to give a colorless solution. Sodium hydride (131 mg, 3.26 mmol, Eq: 2.2) was added. The reaction was stirred at rt for 30 min, then 2-(methylsulfonyl)ethyl methanesulfonate (300 mg, 1.48 mmol, Eq: 1.00) was added and the reaction was stirred at rt overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% EtOAc in hexanes) to give (S)-2-[benzyloxycarbonyl-(2-methanesulfonyl-ethyl)-amino]-propionic acid (201 mg). to give a colorless solution the reaction was stirred at rt overnight The reaction was quenched with saturated aqueous NH4Cl extracted with EtOAc The combined organic layers were washed with water and brine then dried over Na2SO4 concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% EtOAc in hexanes)

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

Procedure: In a 50 mL round-bottomed flask, 2-(methylsulfonyl)ethanol (1.24 g, 9.99 mmol, Eq: 1.00) was combined with DCM (5 mL). To the resulting solution was added diisopropylethylamine (2.1 mL, 12.0 mmol, Eq: 1.2) and methanesulfonyl chloride (1.37 g, 931 μL, 12.0 mmol, Eq: 1.2). The ice bath was removed and the reaction was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 10% to 80% EtOAc in hexanes) to give 2-(methylsulfonyl)ethyl methanesulfonate (1.01 g). The ice bath was removed The crude reaction mixture was concentrated in vacuo the residue was partitioned between EtOAc and water The organic layer was dried over Na2SO4 concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 80 g, 10% to 80% EtOAc in hexanes)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine (1.51 g, 2.44 mmol) and tetrahydrofuran (20 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of s-butyl lithium (3.94 mL, 1.3 M in hexane, 5.12 mmol). After 30 minutes, add a solution of 2-methylsulfonylethyl methanesulfonate (0.60 g, 2.93 mmol). Allow to warm to ambient temperature and then heat to reflux. After 48 hours, cool to ambient temperature and add water. Separate the layers. Extract the aqueous layer four times with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5/0.5/94.5 methanol/concentrated ammonium hydroxide/dichloromethane to give the title compound: Rf=0.54 (silica gel, 5/0.5/94.5 methanol/concentrated ammonium hydroxide/dichloromethane). Allow to warm to ambient temperature heat to reflux After 48 hours cool to ambient temperature Separate the layers Extract the aqueous layer four times with ethyl acetate dry over Na2SO4 filter evaporate in vacuo to give a residue