nuclear magnetic resonance ( nmr ) spectra were acquired using a bruker dpx250 or dpx400 instrument . infra - red spectra were acquired using a nicolet avatar 360 instrument using a germanium atr probe the following liquid chromatography mass spectroscopy ( lcms ) system was used : 3 mm abz + plus ( 3 . 3 cm × 4 . 6 mm internal diameter ) column , eluting with solvents : a - 0 . 1 % formic acid + 0 . 077 % w / v ammonium acetate in water ; and b - 95 : 5 acetonitrile : water + 0 . 05 % v / v formic acid , at a flow rate of 3 ml per minute . the following gradient profile was used : 100 % a for 0 . 7 min ; a + b mixtures , gradient profile 0 - 100 % b over 3 . 5 min ; hold at 100 % b for 1 . 1 min ; return to 100 % a over 0 . 2 min . lc / ms system b 3 μm phenomenex luna ( 50 × 2 mm i . d .) column , eluting with solvents : a - 0 . 05 % trifluoroacetic acid in water , b - 0 . 05 % trifluoroacetic acid in acetonitrile , at 40 ° c . and at a flow rate of 1 ml per minute . the following linear gradient was used : 0 to 95 % b over 8 minutes . reverse - phase high performance liquid chromatography was carried out using a luna 3 mm c18 ( 2 ) ( 50 × 2 . 0 mm i . d .) column eluting with solvents : a - 100 % water , 0 . 05 % tfa ; and b - 100 % acetonitrile , 0 . 05 % tfa , at a flow rate of 2 ml per minute , and at 60 ° c . the following gradient profile was used : 0 - 95 % b over 2 . 00 min , return to 0 % b over 0 . 01 min . 4 -({[({[( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methyl } amino ) carbonyl ] amino }- methyl ) benzamide ( 15 g ) was suspended in ethanol ( 60 ml ) and water ( 7 . 5 ml ) at 40 ° c . a solution of benzene sulfonic acid ( 6 . 0 g ) in water ( 7 . 5 ml ) was added , followed by addition of further water ( 15 ml ). isopropyl acetate ( 300 ml ) was added at 40 ° c ., followed by addition of ethanol ( 40 ml ). the mixture was cooled to 0 ° c ., diluted with cyclohexane ( 10 ml ) and seeded with authentic 4 -({[({[( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methyl } amino ) carbonyl ] amino } methyl ) benzamide benzenesulfonate hydrate . the mixture was chilled at 0 ° c . over 1 h , cyclohexane ( 100 ml ) added over 15 min and the mixture aged at 0 ° c . the product was isolated by vacuum filtration , washed with isopropyl acetate ( 2 × 30 ml ) and dried in vacuo at 25 ± 5 ° to give the title compound as a white solid ( 16 . 44 g ). nmr ( dmso d - 6 ): 2 . 81δ ( 1h ) broad t ; 3 . 0 - 3 . 4δ ( 5h ) m ; 3 . 67δ ( 2h ) m ; 4 . 02δ ( 1h ) d of d , j = 12 . 7 hz , 2 . 5 hz ; 4 . 25δ ( 1h ) d , 5 . 9 hz ; 4 . 37δ ( 2h ) m ; 6 . 24δ ( 1h ) t , j = 5 . 6 hz ; 6 , 58δ ( 1h ) t , j = 5 . 9 hz ; 7 . 3δ ( 6h ) m ; 7 . 48δ ( 1h ) d of d , j = 8 . 3 hz , 2 . 0 hz ; 7 . 61δ ( 2h ) m [ benzene sulphonate ]; 7 . 75δ ( 1h ) d , j = 8 . 3 hz ; 7 . 81δ ( 1h ) d , 2 . 0 hz ; 7 . 82δ ( 2h ) m ; 7 . 91δ ( 1h ) broad s ; 9 . 85 ( 1h ) broad s [ nh + ]. the slurry of description 9 was cooled to 50 ± 3 ° and isopropanol ( 30 ml ) added , followed by an aqueous solution of benzene sulfonic acid ( 32 % w / v , 10 ml ). the mixture was cooled to 22 ± 3 ° over ca 1 h , seeded with authentic 4 -({[({[( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methyl } amino ) carbonyl ] amino } methyl ) benzamide hydrate and aged at 22 ± 3 ° for 72 h . the mixture was cooled to 0 ± 3 ° over 1 h and filtered . the filter cake was washed with a 4 : 1 : 0 . 1 mixture of isopropyl acetate / isopropyl alcohol / water ( 2 . 5 ml ) and dried in vacuo at 25 ± 5 ° to give the title compound as a white solid ( 6 . 9 g ). a solution of 1 -[( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methylamine ( 60 g ) in tetrahydrofuran ( 120 ml ) was added to a suspension of carbonyl diimidazole ( 38 . 8 g ) in tetrahydrofuran ( 600 ml ) over 25 min at 0 - 5 ° c . the mixture was warmed to 10 - 15 ° c ., and held for 15 min . isopropanol ( 30 ml ) was added over 10 min , and the mixture was stirred for a further 45 min at 10 - 15 ° c . 4 - aminomethyl benzamide ( 35 . 9 g ) was added , and the mixture was heated to 55 - 60 ° c ., and held for 90 min . tetrahydrofuran ( 240 ml ) was removed by distillation , and the mixture was cooled to 20 - 25 ° c . the mixture was treated with iso - propyl acetate ( 480 ml ) and 5 % aqueous potassium dihydrogen phosphate ( 480 ml ), and the aqueous phase was removed , the organic phase was washed with further 5 % aqueous potassium dihydrogen phosphate ( 2 × 480 ml ), and finally water ( 480 ml ). the organic phase was concentrated to 250 ml by distillation , diluted with isopropanol ( 850 ml ), and reconcentrated to a final volume of 420 ml . the mixture was cooled to 20 - 25 ° c ., treated with a solution of benzenesulfonic acid ( 38 . 5 g ) in water ( 110 ml ) and warmed to 35 ° c . isopropyl acetate ( 720 ml ) was added , the mixture was cooled to 20 - 25 ° c ., and seeded with authentic 4 -({[({[( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methyl } amino ) carbonyl ] amino }- methyl ) benzamide benzenesulfonate dihydrate . the mixture was stirred for 3 h at this temperature , treated with further iso - propyl acetate ( 180 ml ), stirred for 30 min and cooled to 0 - 5 ° c . the product was isolated by vacuum filtration , washed with isopropyl acetate : isopropanol : water ( 6 : 1 : 0 . 1 , 350 ml ) and dried in vacuo at 35 ± 5 ° to give the title compound as a white solid ( 115 . 6 g ). to a stirred solution of morpholin - 2 - ylmethylamine ( 3 . 1 g ) in methanol ( 70 ml ) under nitrogen was added an ethereal solution of ethyl - α , α , α - trifluoroacetate ( 5 ml in 20 ml ether ) which had been washed with saturated aqueous sodium bicarbonate , water and brine , and dried . the mixture was stirred for 30 min at 22 ° c . before removal of all volatiles in vacuo . the residue was dissolved in methanol ( 10 ml ) and the volatiles again removed in vacuo to give the title compound as a white crunchy foam ( 4 . 9 g ). to a stirred solution of description 1 ( 3 . 3 g ) in n , n - dimethylformamide ( 50 ml ) under nitrogen was added potassium carbonate ( 2 . 46 g ) and sodium iodide ( 2 . 12 g ). a solution of 3 , 4 - dichlorobenzyl chloride ( 2 ml ) in n , n - dimethylformamide ( 10 ml ) was added dropwise to the mixture . the mixture was stirred at 22 ° c . for 18 h before the volatiles were removed in vacuo . the residue was partitioned between dichloromethane ( 100 ml ) and saturated aqueous sodium carbonate solution ( 50 ml ). the organic phase was subsequently washed with additional saturated aqueous sodium carbonate solution ( 2 × 50 ml ) and water ( 50 ml ) before drying over magnesium sulphate , filtering and evaporation of the solvent in vacuo to give a pale yellow oil . the oil was purified by biotage flash chromatography on a 90 g silica cartridge eluting with 25 % ethyl acetate in cyclohexane , to give the title compound as a colourless oil ( 2 . 97 g ). lc / ms ( system a ) r t 2 . 63 min , mass spectrum m / z 371 [ mh + ]. to a stirred solution of description 2 ( 2 . 97 g ) in methanol ( 15 ml ) and water ( 5 ml ) was added potassium carbonate ( 5 . 53 g ). the mixture was stirred at 22 ° c . for 18 h before the methanol was removed in vacuo . water ( 25 ml ) was added and the mixture extracted with ethyl acetate ( 3 × 30 ml ). the combined organic phases were washed with water ( 5 ml ) and saturated aqueous sodium chloride solution ( 10 ml ) before drying over sodium sulphate , filtering and evaporation of the solvent in vacuo to give a pale yellow oil . the oil was purified by biotage flash chromatography on a 90 g silica cartridge eluting with 75 : 8 : 1 dichloromethane / ethanol / 0 . 880 ammonia solution . the required fractions were combined and the solvent evaporated in vacuo to give the title compound as a colourless oil ( 1 . 85 g ). lc / ms ( system a ) r t 1 . 77 min , mass spectrum m / z 275 [ mh + ]. a mixture of 2 -[( 3 , 4 - dichlorobenzyl ) amino ] ethanol ( 0 . 980 g ) and 2 -( oxiran - 2 - ylmethyl )- 1h - isoindole - 1 , 3 ( 2h )- dione ( 1 . 10 g ) was heated at 80 ° c . under nitrogen for 3 h . the resulting solid mass was treated with concentrated sulphuric acid ( 1 . 5 ml ) then stirred at 150 ° c . for 24 h . the mixture was treated with water ( 100 ml ) then washed with ethyl acetate ( 2 × 100 ml ). the dark aqueous phase was basified to ˜ ph 12 using 5m aqueous sodium hydroxide , then extracted with ethyl acetate ( 2 × 100 ml ). the combined organic extracts were washed with water and brine , dried ( na 2 so 4 ) and concentrated under vacuum to give the title compound as a brown oil ( 1 . 02 g ). description 3 ( racemic mixture , 8 g ) was separated into its single enantiomers by preparative chiral - hplc . the separation was carried out using a 2 ″× 22 cm chiralpak ad 20 μm column , merck self pack dac system , eluting with 95 : 5 : 0 . 1 ( v / v ) heptane : absolute ethanol : diethylamine ( flow rate : 55 ml / min over 40 min , uv detection 225 nm ); sample load preparation : 400 mg sample in 20 ml 3 : 2 ( v / v ) absolute ethanol : system eluent . the title compound ( 2 . 49 g ) was obtained as follows : preparative hplc retention time 23 . 0 min . description 3 ( 0 . 613 g ) was dissolved in methanol ( 12 . 3 ml ). d - tartaric acid ( 0 . 335 g ) was added and the slurry was heated to reflux for 50 min . the mixture was allowed to cool to 0 - 5 ° c . and the precipitate isolated by filtration to give the title compound as a white solid ( 0 . 4 g ). ee : 76 % ee chiral analytical hplc ( chiralpak ad column , 4 . 6 × 250 mm , eluent 50 : 50 : 0 . 1 meoh : etoh : butylamine , flow rate 0 . 5 ml / min , uv detection at 220 nm ), rt 8 . 9 min . a mixture of 2 -[( 3 , 4 - dichlorobenzyl ) amino ] ethanol ( 2 . 038 g ) and ( s )- 2 -( oxiran - 2 - ylmethyl )- 1h - isoindole - 1 , 3 ( 2h )- dione ( 2 . 032 g ) in tetrahydrofuran ( 3 . 3 ml ) was stirred and heated at reflux under nitrogen . after 21 . 5 h more tetrahydrofuran ( 12 . 5 ml ) was added and the mixture was cooled to 3 °. triphenyl phosphine ( 2 . 793 g ) was added and the mixture was stirred until all the solid had dissolved . diisopropylazodicarboxylate ( 2 . 1 ml ) was then added over 12 min maintaining the temperature at & lt ; 7 °. after 2 . 25 h the mixture was allowed to warm to 22 °. after 5 . 3 h more triphenylphosphine ( 121 mg ) and diisopropylazodicarboxylate ( 0 . 09 ml ) were added . after 22 . 5 h the reaction mixture was concentrated to near dryness . propan - 2 - ol ( 12 ml ) was added and the concentration repeated , this was repeated once more . more propan - 2 - ol ( 12 ml ) was added and the mixture was heated to 70 °. after 0 . 5 h the slurry was cooled to 22 ° and then after a further 2 h the product was collected . the bed was washed with propan - 2 - ol ( 2 × 4 ml ) and then dried in vacuo at 40 ° to give the title compound ( 2 . 622 g ). nmr ( dmso d - 6 ): 1 . 93δ ( 1h ) d of d , j = 11 . 0 hz , 8 . 8 hz ; 2 . 10δ ( 1h ) d of t , j = 3 . 5 hz , 11 . 3 hz ; 2 . 52δ ( 1h ) broad d , j = 11 . 3 hz ; 2 . 77δ ( 1h ) broad d , j = 11 . 3 hz ; 3 . 3 - 3 . 8δ ( 7h ) m ; 7 . 31δ ( 1h ) d of d , j = 8 . 2 hz , 1 . 9 hz ; 7 . 55δ ( 1h ) d , j = 1 . 9 hz ; 7 . 68δ ( 1h ) d , j = 8 . 2 hz ; 7 . 86δ ( 4h ) m . a slurry of description 7 ( 1 . 00 g ) in water ( 8 . 5 ml ) was heated to 75 ° and then treated dropwise with concentrated sulphuric acid ( 2 . 5 ml ). the mixture was then heated at reflux . after 23 h the reaction mixture was cooled to 22 ° and then treated with dichloromethane ( 6 ml ). 880 ammonia solution ( 7 ml ) was then added dropwise with cooling . more dichloromethane ( 10 ml ) was added . the aqueous phase was separated and extracted with more dichloromethane ( 10 ml ). the combined organic phase was washed with water ( 5 ml ) and then evaporated to dryness . the residue was reevaporated from dcm to give the title compound as an oil ( 662 mg ). nmr ( dmso d - 6 ): 1 . 78δ ( 1h ) t , j = 10 . 5 hz ; 2 . 06δ ( 1h ) d of t , j = 3 . 4 hz , 11 . 3 hz ; 2 . 45 - 2 . 65δ ( 3h ) m ; 2 . 73δ ( 1h ) d of t , j = 11 . 3 hz , 1 . 7 hz ; 3 . 38δ ( 1h ) m ; 3 . 46δ ( 2h ) ab q ; 3 . 51δ ( 1h ) d of d , j = 11 . 3 hz , 2 . 5 hz ; 3 . 77δ ( 1h ) d of m , j = 11 . 3 hz ; 7 . 31δ ( 1h ) d of d , j = 8 . 3 hz , 2 . 0 hz ; 7 . 55δ ( 1h ) d , j = 2 . 0 hz ; 7 . 58δ ( 1h ) d , j = 8 . 3 hz . a solution of ( 5 g ) in thf ( 10 ml ) was added to a slurry of n , n ′- carbonyldiimidazole ( 3 . 2 g ) in thf ( 30 ml ) at 5 - 10 ° c . over ca . 10 min . the mixture was warmed to 15 ± 3 ° and held at this temperature for ca . 15 min . 4 - aminomethyl benzamide ( 3 . 0 g ) was then added , the mixture heated to 60 + 3 ° and stirred at this temp for 75 min . the reaction was cooled to 22 ± 3 ° and isopropyl acetate ( 40 ml ) added , followed by a solution of potassium dihydrogen phosphate ( 5 % w / v , 40 ml ). the solution was filtered through celite ( 2 g ), the lower aqueous layer was removed and the upper organic layer washed with potassium dihydrogen phosphate ( 5 % w / v , 2 × 40 ml ) then water ( 40 ml ). the organic phase was distilled at atmospheric pressure to remove thf and leave a slurry of 4 -({[({[( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methyl } amino ) carbonyl ] amino } methyl ) benzamide in isopropyl acetate ( ca 60 ml ). the slurry containing 4 -({[({[( 2s )- 4 ( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methyl } amino ) carbonyl ] amino } methyl ) benzamide may be used directly for the process of example 2 , or filtered to give 4 -({[({[( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methyl } amino ) carbonyl ] amino } methyl ) benzamide in isolated form for use in the process of example 1 . to a solution of 2 -[ 3 , 4 - dichlorobenzyl ) amino ] ethanol ( 2 . 8 g ) in tetrahydrofuran ( 6 . 2 ml ) is added ( s )- 2 -( oxiran - 2 - ylmethyl )- 1h - isoindole - 1 , 3 ( 2h )- dione ( 3 . 1 g ) with stirring , under a nitrogen atmosphere . the mixture was heated to 90 ° c . over 1 h , then held at this temperature for 18 h . further 2 -[ 3 , 4 - dichlorobenzyl ) amino ] ethanol ( 0 . 14 g ) is added , and the reaction mixture heated to 90 ° c . for a further 5 h . the reaction mixture is cooled to 22 ° c ., and diisopropyl ether ( 21 ml ) added , and the product isolated by vacuum filtration . the filter cake is washed with diisopropyl ether ( 3 ml ) and dried in vacuo at 40 ° to give the title compound as a white solid ( 4 . 79 g ). lc / ms ( system b ) r t 3 . 85 min , mass spectrum m / z 423 [ mh + ] a slurry of description 7 ( 70 . 00 g ) in 40 % w / w aqueous methylamine ( 560 ml ) was heated to 50 - 600 and held for 3 h . the mixture was treated dropwise with 10n sodium hydroxide ( 35 ml ), cooled to & lt ; 25 ° and then treated with dichloromethane ( 210 ml ). the aqueous phase was separated and extracted with more dichloromethane ( 210 ml ). the combined organic phase was washed with water ( 70 ml ) and then evaporated to dryness . the residue was reevaporated from dcm to give the title compound as an oil ( 47 . 7 g ). a mixture of [( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methylamine , 1 : 1 salt with d - tartaric acid ( 20 g ), water ( 100 ml ) and dichloromethane ( 120 ml ) was treated with aqueous ammonia ( 10 ml ) at 15 - 25 ° c . the layers were separated , the aqueous layer was washed with dichloromethane ( 30 ml ) and the combined organic layers were washed with 2 % aqeous sodium chloride ( 20 ml ). the organic phase was concentrated to an oil , and taken up in thf ( 20 ml ). this solution was added to a slurry of n , n ′- carbonyldiimidazole ( 7 . 8 g ) in thf ( 80 ml ) at 0 - 5 ° c . over ca . 10 min . the mixture was warmed to 15 ± 3 ° and held at this temperature for ca . 15 min . isopropanol ( 6 ml ) was added , and stirred for a further 5 min at 15 ± 3 °. 4 - aminomethyl benzamide ( 7 . 2 g ) was then added , the mixture heated to 60 ± 3 ° and stirred at this temp for 120 min . the reaction was cooled to 22 ± 3 ° and isopropyl acetate ( 96 ml ) added , followed by a solution of potassium dihydrogen phosphate ( 5 % w / v , 96 ml ). the organic phase was washed with further potassium dihydrogen phosphate ( 5 % w / v , 2 × 96 ml ), and then water ( 96 ml ). the organic phase was filtered through celite , and the cake was washed with isopropyl acetate . the filtrate was concentrated to a semi - solid and resuspended in isopropyl acetate ( 200 ml ) at reflux . the slurry was cooled to 20 - 25 ° c . over 1 h , cooled to 0 - 5 ° c . and aged for 15 min . the product was isolated by filtration , washed with isopropyl acetate ( 50 ml ) and dried in vacuo to give the title compound as a white solid ( 17 . 4 g ). lc - ms ( system a ) r t 2 . 27 min , mass spectrum m / z 451 / 453 ( mh +) a mixture of 2 -[( 3 , 4 - dichlorobenzyl ) amino ] ethanol ( 400 g ) and ( s )- 2 -( oxiran - 2 - ylmethyl )- 1h - isoindole - 1 , 3 ( 2h )- dione ( 399 . 6 g ) in toluene ( 1150 ml ) was stirred and heated at 103 - 107 ° c . under nitrogen . after 22 . 5 h the mixture was cooled to & lt ; 60 ° c . and charged with tetrahydrofuran ( 2800 ml ). triphenyl phosphine ( 548 g ) was added and the mixture was stirred until all the solid had dissolved , then cooled to 5 - 9 ° c . diisopropylazodicarboxylate ( 412 ml ) was then added over 70 min maintaining the temperature at & lt ; 12 °. the mixture was warmed to 21 - 25 ° and stirred for 1 . 5 h . the reaction mixture was concentrated by distillation to a final volume of 2800 ml . methanol ( 2800 ml ) was added and the concentration repeated to a volume of 2800 ml . more methanol ( 2000 ml ) was added and the mixture was heated to 55 °. after 0 . 75 h the slurry was cooled to 18 ° and then after a further 1 h the product was collected . the bed was washed with methanol ( 2 × 1200 ml ) and then dried in vacuo at 40 ° to give the title compound ( 526 . 9 g ). x - ray diffraction data for ( 4 -({[({[( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methyl } amino ) carbonyl ] amino } methyl ) benzamide benzenesulfonate dihydrate is shown in fig1 . table 1 below sets out the instrument and parameters used . table 2 below sets out the peak listings . the stability of 4 -({[({[( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methyl } amino ) carbonyl ] amino } methyl ) benzamide benzenesulfonate dihydrate was measured using differential scanning calorimetry . table 3 sets out the instrument and parameters used and the results are shown in fig2 and 3 . the stability of 4 -({[({[( 2s )- 4 -( 3 , 4 - dichlorobenzyl ) morpholin - 2 - yl ] methyl } amino ) carbonyl ] amino } methyl ) benzamide benzenesulfonate dihydrate was measured using thermogravimetric analysis . table 4 sets out the instrument and parameters used and the results are shown in fig4 .