N-(4-hydroxyphenyl)methanesulfonamide

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

Procedure: A solution of 22.63 g (0.25 mol) of acryloyl chloride in 250 ml of methylene chloride was added over a period of 35 minutes to a mixture of 46.81 g (0.25 mol) of N-(4-hydroxyphenyl)methanesulfonamide, 25.30 g (0.25 mol) of triethylamine and 750 ml of methylene chloride at 0° C. The resultant solution was stirred at reduced temperature for 2.17 hours, washed three times with water and dried over magnesium sulfate. Concentration of the solution in vacuo gave a solid which after two recrystallizations from benzene and drying gave 13.4 g (22.2 percent yield) of N-(4-acryloyloxyphenyl)methanesulfonamide; m.p.=136.5° to 139.5° C. washed three times with water dried over magnesium sulfate Concentration of the solution in vacuo gave a solid which after two recrystallizations from benzene drying

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

Procedure: A solution of 22.63 g (0.25 mol) of acryloyl chloride in 250 ml of methylene chloride was added over a period of 35 minutes to a mixture of 46.81 g (0.25 mol) of N-(4-hydroxyphenyl)methanesulfonamide, 25.30 g (0.25 mol) of triethylamine and 750 ml of methylene chloride at 0° C. The resultant solution was stirred at reduced temperature for 2.17 hours, washed three times with water and dried over magnesium sulfate. Concentration of the solution in vacuo gave a solid which after two recrystallizations from benzene and drying gave 13.4 g (22.2 percent yield) of N-(4-acryloyloxyphenyl)methanesulfonamide; m.p.=136.5° to 139.5° C. washed three times with water dried over magnesium sulfate Concentration of the solution in vacuo gave a solid which after two recrystallizations from benzene drying

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.4 g (49.5 mmol) of p-aminophenol are dissolved in 40 ml of anhydrous pyridine, and 5.7 g (1 equivalent) of methanesulfonyl chloride diluted in 12 ml of pyridine are added over 15 minutes at 20° C. under a stream of nitrogen. The reaction medium is stirred for 3 days at 20° C. and is then poured into 1.5 liters of water containing a sufficient amount of hydrochloric acid (67 g of 36% HCl) to neutralize the pyridine and to establish a pH≦1.5. The aqueous phase is separated out by settling and extracted twice with 250 ml of ethyl acetate. The organic phases are combined and washed with twice 250 ml of water and then concentrated under vacuum. The residue is recrystallized from 40 ml of ethyl acetate. The crystals are filtered off at 0° C. and washed with 15 ml of ethyl acetate. 2.14 g of crude p-methanesulfonamidophenol are obtained. are added over 15 minutes at 20° C. under a stream of nitrogen The aqueous phase is separated out extracted twice with 250 ml of ethyl acetate washed with twice 250 ml of water concentrated under vacuum The residue is recrystallized from 40 ml of ethyl acetate The crystals are filtered off at 0° C. washed with 15 ml of ethyl acetate

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

Procedure: To a stirred solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)carbonyloxy)ethyl)pyridine 1-oxide (prepared in an analogous manner to that described in Example 45, Step 4) (0.140 g, 0.239 mmol) in DCM (5 ml), a solution of N-(4-hydroxyphenyl)-methanesulfonamide (0.0672 g, 0.359 mmol) and DMAP (0.0438 g, 0.359 mmol) in DCM (5 ml) was added drop wise, and the reaction was stirred at RT for 3 hours. The solvent was evaporated and the resulting crude was purified by chromatography on silica gel column (DCM:MeOH=10:0.4). A second purification by crystallization from absolute ethanol was required to obtain (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-(methylsulfonamido)-phenoxy)carbonyloxy)ethyl)pyridine 1-oxide as a brown solid (0.050 g, 0.079 mmol, 33% yield, MS/ESI+ 632.74 [MH]+, [αD]=−36.59, c=0.252, DCM). The solvent was evaporated the resulting crude was purified by chromatography on silica gel column (DCM:MeOH=10:0.4) A second purification by crystallization from absolute ethanol

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

Procedure: To a cold suspension of 4-aminophenol (5.45 g, 49.9 mmol) in MeOH (62 ml), methanesulfonyl chloride (1.95 ml, 25.2 mmol) was added under stirring maintaining the temperature between 10 and 15° C. The resulting solution was allowed to warm to RT and stirred for 2 hours. The solvent was removed under vacuum, and the residue was suspended in HCl 1N (62 ml); the insoluble was collected by filtration, washed with water, dried and purified by filtration through a silica gel pad (DCM:MeOH=100:15) affording N-(4-hydroxyphenyl)methanesulfonamide as a brown solid (1.35 g, 7.21 mmol, 28.6% yield). was added maintaining the temperature between 10 and 15° C stirred for 2 hours The solvent was removed under vacuum the insoluble was collected by filtration washed with water dried purified by filtration through a silica gel pad (DCM:MeOH=100:15)

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

Procedure: A solution of 22.63 g (0.25 mol) of acryloyl chloride in 250 ml of methylene chloride was added over a period of 35 minutes to a mixture of 46.81 g (0.25 mol) of N-(4-hydroxyphenyl)methanesulfonamide, 25.30 g (0.25 mol) of triethylamine and 750 ml of methylene chloride at 0° C. The resultant solution was stirred at reduced temperature for 2.17 hours, washed three times with water and dried over magnesium sulfate. Concentration of the solution in vacuo gave a solid which after two recrystallizations from benzene and drying gave 13.4 g (22.2 percent yield) of N-(4-acryloyloxyphenyl)methanesulfonamide; m.p.=136.5° to 139.5° C. washed three times with water dried over magnesium sulfate Concentration of the solution in vacuo gave a solid which after two recrystallizations from benzene drying