Patent Application: US-80869308-A

Abstract:
aspirin is one of the most widely used drugs in the treatment of inflammation , pain and fever . it has more recently found application in the prevention of heart attacks and stroke and is being studied as a cancer chemopreventative agent . despite its value aspirin continues to be underutilized because it causes gastric bleeding . the technology under development potentially removes this problem . it is designed to reduce contact between the drug and the intestinal lining . an isosorbide aspirinate prodrug compound is thus provided . the compound has the general structure as shown in general formula wherein y is a c 1 - c 8 alkyl ester , a c 1 - c 8 alkoxy ester , a c 3 - c 10 cycloalkyl ester , an arylester , a c 1 - c 8 alkylaryl ester or — cor ring , wherein r ring is a 5 - membered aromatic or nonaromatic 5 - member ring having at least one heteroatom substituted for a carbon of the ring system , which can be unsubstituted or substituted with at least one nitric oxide releasing group .

Description:
5 - ismn was obtained from sifa ltd . purified human serum butyrylcholinesterase ( ec 3 . 1 . 1 . 8 ), rabbit liver carboxylesterase ( ec 3 . 1 . 1 . 1 ), bnpp ( bis - 4 - nitrophenylphosphate ), iso - ompa ( tetraisopropylpyrophosphoramide ), pooled human liver microsomes , 3 - chloromethylbenzoyl chloride , 4 - chloromethylbenzoyl chloride , silver nitrate , phthalide , dichlorotriphenylphosphorane and hplc grade solvents were obtained from sigma - aldrich . collagen and adp was obtained from chronolog ( havertown , pa ., u . s . a .). allophycocyanin ( apc )- conjugated monoclonal antibody against high - affinity gpiib / iiia ( pac - 1 - apc ) and apc - conjugated monoclonal antibody against human platelet p selectin ( cd62p ) were purchased from bd biosciences ( oxford , uk ). all other solvents and reagents were analytical grade . pooled human intestinal microsomes were obtained from bd gentest in the uk . the compounds of the invention are easily prepared from isosorbide - mono - nitrate aspirinate ( ismna ), itself prepared by esterification of isosorbide - mono - nitrate ( ismn ) with and acetyl salicoyl chloride according to gilmer et al 2001 . the nitrate is selectively removed by treatment with palladium on carbon under an atmosphere of hydrogen generating the key intermediate isosorbide - 2 - aspirinate . the compounds may also be obtained by selective 5 - esterification of isosorbide followed by attachment of the aspirinate group at position - 2 ( the 5 - position in isosorbide despite being endo is more reactive towards acylation than the 2 - exo position because the 5 - oh is activated by an intramolecular h - bond ) in the case of isosorbide - 2 - aspirinate - 5 - salicylate ( isas ) direct acylation with salicylic acid would be complicated by competition between the salicylate - oh and the isosorbide - oh . consequently a benzyl - ether protected salicylic acid is introduced first using standard dcc coupling procedure and the benzyl protection removed under reductive conditions ( fig1 ). other ester compounds of the invention can be prepared by directed acylation using dcc coupling or by treatment with the appropriate acid chloride in the presence of a tertiary base such as triethylamine . nitroxy - substituted esters may be prepared by linking directly to the appropriately substituted acids . alternatively , nitroxy - substituted compounds may be obtained by first esterifying with an acid bearing a chloride or bromide which can be subsequently displaced by nitrate by treatment with agno 3 in acetonitrile . to a solution of isosorbide - 2 - aspirinate 17 ( 0 . 2 g , 0 . 65 mmol ) in dichloromethane ( 15 ml ) was added triethylamine ( 0 . 11 ml , 0 . 98 mmol ) and 2 - toluoyl chloride ( 0 . 09 ml , 0 . 72 mmol ). the reaction mixture was stirred at room temperature for 24 hours and then was washed with water ( 2 × 25 ml ), hcl ( 1 m , 25 ml ) and saturated aqueous nahco 3 before drying over anhydrous mgso 4 . solvent was removed in vacuo to give 0 . 41 g of crude product as brown oil . purification by column chromatography using hexane and ethyl acetate ( 2 : 1 ) as eluant gave product as yellow oil . this was recrystallised in ethanol to yield compound 1 as a white solid ( 0 . 11 g , 39 . 6 %) m pt . 104 - 106 ° c . ir vmax ( kbr ): 2987 . 1 and 2922 . 8 ( c — h stretching ), 1762 . 0 and 1718 . 1 ( c ═ o ), 1259 . 5 and 1199 . 8 ( c ( o ) or aromatic ), 1072 . 4 ( c — o — c ) cm − 1 . hrms : requires : 449 . 1212 ( m + + 23 ), found : 449 . 1238 ( m + + 23 ), 1 h nmr δ ( cdcl 3 ): 2 . 38 ( 3h , s , ococh3 ), 2 . 65 ( 3h , s , arch 3 ), 4 . 01 ( 1h , dd , j 5 . 52 and 5 . 52 hz , is6 - h [ α ]), 4 . 12 ( 3h , m , is1h [ αβ ] and is6h [ β ]), 4 . 66 ( 1h , d , j 4 . 52 hz , ish - 3 ), 5 . 04 ( 1h , t , j 5 . 04 and 5 . 0 hz , ish - 4 ), 5 . 41 ( 1h , q , j 5 . 52 , 5 . 52 and 5 . 52 hz , ish - 5 ), 5 . 47 ( 1h , d , j 2 . 0 hz , ish - 2 ), 7 . 13 ( 1h , dd , j 1 . 0 and 1 . 0 hz , arh - 4 ), 7 . 33 ( 1h , t , j 7 . 0 and 6 . 52 hz , arh - 2 ), 7 . 59 ( 1h , t , j 6 . 52 and 6 . 52 hz , arh - 3 ), 8 . 02 ( 1h , dd , j 1 . 52 and 2 . 0 hz , arh - 1 ). 13 c nmr ppm ( cdcl 3 ): 20 . 43 ( ar — ch 3 ), 21 . 12 ( oco c h 3 ), 70 . 29 ( isc - 1 ), 72 . 72 ( isc - 6 ), 73 . 81 ( o c ( o ) ar ), 78 . 22 ( isc - 4 ), 80 . 52 ( isc - 2 ), 85 . 63 ( isc - 3 ), 122 . 32 ( ar 1 c - 1 ), 123 . 38 ( ar 1 c - 4 ), 125 . 58 ( ar 1 c - 2 and ar 2 c - 4 ), 128 . 46 ( ar 2 c - 2 and ar 2 c - 5 ), 130 . 19 ( ar 2 c - 3 ), 133 . 78 ( ar 1 c - 3 ), 140 . 08 ( ar 2 c - 1 ), 150 . 26 ( ar 1 c - 5 ), 163 . 12 ( aro c ome ), 169 . 15 ( ar c oor ) 2 - benzyloxybenzoic acid ( 364 . 8 mg = 1 . 6 mmol ) was dissolved in dry dcm ( 20 mls ) and stirred . is - 2 - asp - 5 - oh ( 500 mg = 1 . 6 mmol ) and 10 % dmap was added . the flask was cooled to 0 ° c . and dcc ( 340 mg , 1 . 6 mmol ) was added . stirring was continued for five minutes and the temperature was allowed to come to room temperature where it was stirred over night . the reaction was filtered and the filtrate was washed with 0 . 1m hcl , 5 % nahco 3 and water . dried over sodium sulfate and evaporated to an oil . this was purified by column chromatography hexane / ethyl acetate ( 2 : 1 ) to give a white product ( rf = 0 . 4 , 228 mg ). this was dissolved in methanol / ethyl acetate ( 1 : 1 ). pd / c was added and the reaction was stirred under hydrogen over night . reaction was filtered and concentrated . oil was purified by column chromatography using hexane / ethyl acetate ( 1 : 1 ) to yield a white solid ( 107 mg rf = 0 . 67 )). 1 h nmr δ ( cdcl 3 ) 400 mhz : 2 . 38 ( 3h , s , ococ h 3 ), 4 . 02 ( 4h , m , ish - 1 , ish - 1 ′, ish - 6 and ish - 6 ′), 4 . 63 ( 1h , d , ish - 3 ), 5 . 03 ( 1h , t , ish - 4 ), 5 . 43 ( 2h , dd , ish - 2 , ish - 5 ), 6 . 91 ( 1h , t , ar — h ), 7 . 01 ( 1h , d , ar — h ), 7 . 1 ( 1h , d , ar — h ), 7 . 28 ( 1h , t , ar — h ), 7 . 48 ( 1h , t , ar — h ), 7 . 53 ( 1h , t , ar — h ), 7 . 89 ( 1h , d , arh ), 8 . 00 ( 1h , d , arh ), 10 . 61 ( 1h , s , oh ). 13 c nmr ppm ( cdcl 3 ) 400 mhz : 20 . 51 ( oco c h 3 ), 70 . 46 ( isc - 1 ), 72 . 78 ( isc - 6 ), 74 . 31 ( isc - 5 ), 77 . 91 ( isc - 2 ), 80 . 69 ( isc - 4 ), 85 . 70 ( isc - 3 ), 117 . 30 ( ar 2 c - 1 ), 118 . 90 , 123 . 41 , 125 . 65 , 129 . 47 , 131 . 42 , 133 . 94 , 135 . 65 , 150 . 24 ( ar 1 c - 2 ), 163 . 12 ( aro c och 3 ), 168 . 87 ( ar c ( o ) or ). isosorbide - 2 - aspirinate 17 ( 0 . 2 g , 0 . 65 mmol ) was dissolved in toluene ( 15 ml ) at 0 ° c ., to which was added dcc ( 0 . 13 g , 0 . 65 mmol ) and dmap ( 0 . 08 g , 0 . 07 mmol ). after 10 mins the reaction vessel was returned to room temperature and 3 - toluic acid ( 0 . 09 g ) was added and allowed to stir for 24 hours . after washing with hcl ( 30 ml , 1m ), saturated aqueous nahco 3 ( 30 ml ), saturated brine solution ( 30 ml ) and water ( 3 × 30 ml ) the reaction mixture was dried over anhydrous na 2 so 4 and solvent removed in vacuo to yield crude product as a clear oil . purification by column chromatography using hexane and ethyl acetate ( 3 : 2 ) as eluant yielded compound 3 as white crystals ( 0 . 12 g , 43 . 2 %): m . pt . 96 - 98 ° c . ir vmax ( kbr ): 2987 . 1 and 2922 . 8 ( c — h stretching ), 1762 . 0 and 1718 . 1 ( c ═ o ), 1259 . 5 and 1199 . 8 ( c ( o ) or , aromatic ), 1072 . 4 ( c — o — c ) cm − 1 . hrms : requires : 449 . 1212 ( m + + 23 ), found : 449 . 1234 ( m + + 23 ), 1 h nmr δ ( cdcl 3 ): 2 . 36 ( 3h , s , ococh 3 ), 2 . 43 3h , s , arch 3 ), 4 . 09 ( 4h , m , is1 - h 2 [ α + β ] and is6 - h 2 [ α + β ]), 4 . 65 ( 1h , d , j 5 . 0 hz , ish - 3 ), 5 . 04 ( 1h , t , j 5 . 04 and 5 . 0 hz , ish - 4 ), 5 . 43 ( 2h , m , ish - 5 and ish - 2 ), 7 . 12 ( 1h , d , j 8 . 0 hz , arh - 4 ), 7 . 35 ( 3h , m , arh - 2 ), 7 . 58 ( 1h , q , j 1 . 0 , 6 . 56 and 1 . 48 hz , arh - 3 ), 8 . 01 ( 1h , dd , j 1 . 0 and 1 . 52 hz , arh - 1 ). 13 c nmr ppm ( cdcl 3 ): 20 . 42 ( ar c h 3 ), 20 . 79 ( oco c h 3 ), 70 . 39 ( isc - 1 ), 72 . 77 ( isc - 6 ), 73 . 92 ( isc - 5 ), 78 . 19 ( isc - 4 ), 80 . 66 ( isc - 2 ), 85 . 66 ( isc - 3 ), 122 . 35 ( ar 1 c - 1 ), 123 . 39 ( ar 1 c - 4 ), 125 . 57 ( ar 1 c - 6 ), 126 . 45 ( ar 1 c - 2 ), 12 . 89 ( ar 2 c - 4 ), 129 . 80 ( ar 2 c - 5 ), 131 . 37 ( ar 2 c - 3 ), 133 . 77 ( ar 2 c - 1 ), 150 . 25 ( ar 1 c - 5 ), 163 . 15 ( aro c och 3 ), 165 . 58 ( iso c oar ), 169 . 12 ( aro c o ). to a solution of isosorbide - 2 - aspirinate 17 ( 0 . 2 g , 0 . 65 mmol ) in dichloromethane ( 20 ml ) was added triethylamine ( 0 . 09 ml , 0 . 65 mmol ) and acetic anhydride ( 0 . 06 ml , 0 . 65 mmol ). the reaction vessel was stirred at room temperature for 24 hours before washing with water ( 2 × 20 ml ), hcl ( 1m , 30 ml ), saturated aqueous nahco 3 ( 30 ml ) and drying over mgso 4 . solvent was removed by rotary evaporation to yield 0 . 52 g of crude product . purification by column chromatography using hexane and ethyl acetate ( 3 : 2 ) as eluant afforded compound 4 as white crystalline material ( 0 . 1 g , 43 . 8 %). m . pt . 96 - 98 ° c . ir vmax ( kbr ): 2966 . 9 and 2928 . 6 ( c — h stretching ), 1751 . 6 and 1734 . 0 ( c ═ o ), 1607 . 8 ( c ═ c stretching ), 1262 . 0 and 1193 . 9 ( c ( o ) or aromatic ), 1082 . 5 ( c — o — c ) cm − 1 . hrms : requires : 373 . 0899 ( m + + 23 ), found : 373 . 0877 ( m + + 23 ), 1 h nmr δ ( cdcl 3 ): 2 . 13 ( 3h , s , is — ococh 3 ), 2 . 37 ( 3h , s , ar — ococh 3 ), 3 . 85 ( 1h , q , j 5 . 52 , 4 . 52 and 4 . 96 hz , is6α - h ), 3 . 99 ( 1h , q , j 6 . 0 , 3 . 52 and 6 . 04 hz , is6β - h ), 4 . 10 ( 2h , t , j 3 . 52 and 2 . 0 hz , is1h 2 [ α + β ]), 4 . 59 ( 1h , d , j 4 . 52 hz , ish - 3 ), 4 . 90 ( 1h , t , j 5 . 0 and 5 . 04 hz , ish - 4 ), 5 . 19 ( 1h , d , j 5 . 52 hz , ish - 5 ), 5 . 44 ( 1h , d , j 5 . 52 hz , ish - 2 ), 7 . 12 ( 1h , d , j 8 . 04 hz , arh - 4 ), 7 . 33 ( 1h , t , j 7 . 52 and 7 . 56 hz , arh - 2 ), 7 . 59 ( 1h , m , arh - 3 ), 8 . 01 ( 1h , dd , j 6 . 04 hz , arh - 1 ). 13 c nmr ppm ( cdcl 3 ): 20 . 43 ( arococh 3 ), 20 . 18 ( is — ococh 3 ), 69 . 91 ( isc - 2 ), 72 . 78 ( isc - 6 ), 73 . 52 ( isc - 5 ), 78345 ( isc - 3 ), 80 . 32 ( isc - 1 ), 122 . 29 ( arc - 5 ), 123 . 39 ( arc - 1 ), 125 . 58 ( arc - 3 ), 131 . 36 ( arc - 2 ), 133 . 81 ( arc - 4 ), 154 . 32 ( arc - 6 ), 167 . 15 ( o c oar ), 168 . 48 ( aro c och 3 ), 171 . 27 ( o c och 3 ). isosorbide - 2 - aspirinate 17 ( 0 . 3 g , 0 . 98 mmol ) was dissolved in dichloromethane ( 20 ml ) to which was added proprionic anhydride ( 0 . 14 ml , 1 . 07 mmol ) and triethylamine ( 0 . 09 ml , 1 . 07 mmol ). this was allowed to stir at room temperature for 24 hours before washing with hcl ( 30 ml , 1m ), saturated aqueous nahco 3 ( 30 ml ) and water ( 2 × 30 ml ). reaction was dried over anhydrous na 2 so 4 and solvent was removed in vacuo to yield crude product as a yellow oil ( 0 . 19 g ). purification by column chromatography using hexane and ethyl acetate ( 5 : 2 ) as eluant yielded product as white crystals ( 0 . 3 g , 84 . 3 %): m . pt . 54 - 56 ° c . ir vmax ( kbr ): 2989 . 0 and 2933 . 0 ( c — h stretching ), 1764 . 0 and 1734 . 5 ( c ═ o ), 1606 . 3 ( c ═ c stretching ), 1254 . 3 and 1193 . 6 ( c ( o ) or , aromatic ), 1080 . 6 ( c — o — c ) cm − 1 . hrms : requires : 387 . 1056 ( m + + 23 ), found : 387 . 1069 ( m + + 23 ). 1 h nmr δ ( cdcl 3 ): 1 . 19 ( 3h , t , j 8 . 04 and 7 . 52 hz , ch 3 ), 2 . 37 ( 3h , s , ococh 3 ), 2 . 44 ( 2h , q , j 7 . 52 , 8 . 04 and 7 . 52 hz , och 2 ), 3 . 86 ( 1h , q , j 5 . 52 , 4 . 52 and 5 . 04 hz , is6α - h ), 3 . 98 ( 1h , q , j 5 . 52 , 4 . 04 and 6 . 0 hz , is6β - h ), 4 . 08 ( 2h , m , is1h 2 [ α + β ]), 4 . 59 ( 1h , d , j 4 . 52 hz , ish - 3 ), 4 . 91 ( 1h , t , j 5 . 0 and 5 . 04 , ish - 4 ), 5 . 20 ( 1h , q , j 5 . 04 , 6 . 0 and 5 . 52 hz , ish - 5 ), 5 . 43 ( 1h , d , j 3 . 0 hz , ish - 2 ), 7 . 12 ( 1h , dd , j 1 . 0 and 1 . 0 hz , arh - 4 ), 7 . 33 ( 1h , t , j 1 . 0 , 6 . 56 and 8 . 0 hz , arh - 2 ), 7 . 59 ( 1h , t , j 6 . 0 and 6 . 52 hz , arh - 3 ), 8 . 01 ( 1h , dd , j 1 . 48 and 2 . 0 hz , arh - 1 ). 13 c nmr ppm ( cdcl 3 ): 8 . 62 ( ch 2 c h 3 ), 20 . 49 ( co c h 3 ), 26 . 84 ( oco c h 2 ), 70 . 08 ( isc - 2 ) 72 . 72 ( isc - 6 ), 73 . 32 ( isc - 5 ), 78 . 12 ( isc - 3 ), 80 . 37 ( isc - 1 ), 85 . 45 ( isc - 4 ), 122 . 22 ( arc - 5 ), 123 . 41 ( arc - 1 ), 125 . 64 ( arc - 3 ), 131 . 41 ( arc - 2 ), 133 . 89 ( arc - 4 ), 150 . 24 ( arc - 6 ), 163 . 09 ( o c oar ), 169 . 28 ( o c och 3 ), 173 . 40 ( o c och 2 ). to a solution of isosorbide - 2 - aspirinate 17 ( 1 . 0 g , 3 . 25 mmol ) in dichloromethane ( 20 ml ) was added benzoic acid ( 0 . 59 g , 4 . 88 mmol ), dcc ( 1 . 34 g , 6 . 49 mmol ) and dmap ( 0 . 38 g , 3 . 11 mmol ). the reaction mixture was allowed to stir at room temperature for three hours before filtering off precipitate and washing the filtrate with hcl ( 30 ml , 1m ), saturated aqueous na 2 hco 3 ( 30 ml ) and water ( 3 × 30 ml ). it was dried over anhydrous na 2 so 4 and solvent was removed in vacuo to give colourless oil , which was recrystallised in ethanol to afford product as white crystals ( 1 . 13 g , 84 . 3 %): m . pt . 80 - 82 ° c . ir vmax ( kbr ): 2991 . 1 and 2932 . 9 ( c — h , stretching ), 1762 . 9 and 1720 . 6 ( c ═ o ), 1275 . 5 and 1199 . 1 ( c ( o ) or aromatic ), 1078 . 4 ( c — o — c ) cm − 1 . hrms : requires : 435 . 1056 ( m + + 23 ), found : 435 . 1043 ( m + + 23 ). 1 h nmr δ ( cdcl 3 ): 2 . 37 ( 3h , s , ococh 3 ), 4 . 07 ( 1h , m , is1α - h ), 4 . 11 ( 3h , m , is6h [ α +] and is1β - h ), 4 . 65 ( 1h , d , j 5 . 0 hz , ish - 5 ), 5 . 05 ( 1h , t , j 5 . 5 and 5 . 0 hz , ish - 3 ), 5 . 56 ( 1h , m , ish - 4 ), 7 . 13 ( 1h , d , j 8 . 04 hz , ar 1 h1 - 5 and ar 1 h - 3 ), 7 . 27 ( 1h , t , j 8 . 04 and 6 . 52 hz , ar 2 h — and ar 2 h - 5 ), 7 . 33 ( 1h , d , j 7 . 56 hz , ar 1 h - 4 ), 7 . 49 ( 2h , t , j 7 . 52 and 7 . 56 hz , ar 2 h - 5 ), 8 . 01 ( 1h , d , j 7 . 56 hz , ar 1 h1 - 2 ), 8 . 12 ( 2h , d , j 7 . 52 hz , ar 2 h - 2 and ar 2 h - 6 ). 13 c nmr ppm ( cdcl 3 ): 20 . 44 ( oco c h 3 ), 70 . 42 ( isc - 1 ), 72 . 79 ( isc - 6 ), 73 . 97 ( isc - 5 ) 78 . 16 isc - 2 ), 80 . 67 ( isc - 4 ), 85 . 67 ( isc - 3 ), 123 . 39 ( ar 1 c - 5 ), 125 . 58 ( ar 1 c - 1 ), 128 . 00 ( ar 1 c - 3 ), 129 . 31 ( ar 2 c - 3 and ar 2 c - 5 ), 131 . 39 ( ar 1 c - 2 and ar 2 c - 6 ), 132 . 82 ( ar 2 c - 2 and ar 2 c - 1 ), 133 . 79 ( ar 2 c - 4 ), 134 . 81 ( ar 1 c - 4 ), 154 . 32 ( ar 1 c - 6 ), 167 . 10 ( o c och 3 ), 168 . 2 ( o c oar 1 and o c oar 2 ). isosorbide - 2 - aspirinate 17 ( 0 . 3 g , 0 . 98 mmol ), in dichloromethane ( 20 ml ) at 0 ° c . was stirred for 10 mins in the presence of dcc ( 0 . 2 g , 0 . 98 mmol ) and dmap ( 0 . 12 g , 0 . 98 mmol ). the reaction vessel was returned to room temperature , nicotinic acid ( 0 . 12 g , 0 . 98 mmol ) was added and allowed to stir for 24 hours . the reaction mixture was washed with hcl ( 20 ml , 1m ), saturated aqueous nahco 3 ( 20 ml ), water ( 3 × 20 ml ), dried over anhydrous na 2 so 4 and solvent removed in vacuo to give product as a crude oil ( 0 . 95 g ). purification by column chromatography over silica gel using dichloromethane and ethyl acetate ( 95 : 5 ) as eluant yielded compound 7 as white crystals ( 0 . 12 g , 29 . 7 %): m . pt . 94 - 96 ° c . ir vmax ( kbr ): 3327 . 6 ( n ═ c ), 2929 . 6 ( c — h stretching ), 1731 . 7 and 1718 . 7 ( c ═ o ), 1654 . 4 ( c ═ c stretching ), 180 . 7 and 1195 . 9 ( c ( o ) or aromatic ), 1090 . 4 ( c — o — c ) cm − 1 . hrms : requires : 436 . 1008 ( m + + 23 ), found : 436 . 1011 ( m + + 23 ). 1 h nmr δ ( cdcl 3 ): 2 . 36 ( 3h , s , ococh 3 ), 4 . 11 ( 9h , m , is1 - h 2 [ α + β ] and is6 - h 2 [ α + β ]), 6 . 64 ( 1h , d , j 4 . 52 hz , ish - 3 ), 5 . 05 ( 1h , t , j 5 . 04 and 5 . 52 hz , ish - 4 ), 5 . 46 ( 2h , dd , j 2 . 0 and 2 . 52 hz , ish - 5 and ish - 2 ), 7 . 11 ( 1h , d , j 8 . 52 hz , ar 1 h - 2 ), 7 . 32 ( 1h , q , j 6 . 52 , 8 . 04 and 8 . 52 hz , ar 1 h - 3 ), 7 . 43 ( 1h , q , j 6 . 53 , 8 . 04 and 8 . 52 hz , ar 1 h - 5 ), 7 . 59 ( 1h , t , j 6 . 04 and 6 . 52 hz , ar 1 h - 4 ), 8 . 00 ( 1h , dd , j 1 . 52 and 2 . 0 hz , ar 2 h - 5 ), 8 . 34 ( 1h , m , ar 2 h - 6 ), 8 . 82 ( 1h , dd , j 2 . 0 and 1 . 48 hz , ar 2 h - 4 ), 9 . 28 ( 1h , d , j 2 . 0 hz , ar 2 h - 2 ). 13 c nmr ppm ( cdcl 3 ): 20 . 52 ( oco c h 3 ), 79 . 32 ( isc - 1 ), 72 . 75 ( isc - 6 ), 74 . 38 ( iso c ( o ) ar ), 74 . 43 ( isc - 5 ), 78 . 27 ( isc - 4 ), 80 . 60 ( isc - 2 ), 85 . 60 ( isc - 3 ), 122 . 26 ( ar 1 c - 1 ), 122 . 88 ( ar 1 c - 4 ), 123 . 38 ( ar 2 c - 4 ), 125 . 57 ( ar 1 c - 6 ), 131 . 35 ( ar 2 c - 6 ), 133 . 83 ( ar 1 c - 2 ), 136 . 68 ( ar 1 c - 3 ), 150 . 55 ( ar 2 c - 5 ), 153 . 30 ( ar 2 c - 1 ), 164 . 13 ( ar 1 c - 5 ), 164 . 13 ( ar 2 c - 3 ), 170 . 59 ( ar c oor ). isosorbide - 2 - aspirinate 17 ( 0 . 2 g , 0 . 65 mmol ) was dissolved in dichloromethane ( 20 ml ) at 0 ° c . to which was added dcc ( 0 . 13 g , 0 . 65 mmol ) and dmap ( 0 . 08 g , 0 . 65 mmol ). after 10 mins the reaction vessel was returned to room temperature and iso - nicotinic acid ( 0 . 08 g , 0 . 65 mmol ) was added and stirred for 24 hours . the reaction was washed with hcl ( 20 ml , 1m ), saturated aqueous nahco 3 ( 20 ml ), water ( 3 × 20 ml ), dried over anhydrous mgso 4 and solvent removed in vacuo to yield compound 8 as white powder ( 0 . 17 g , 63 . 1 %): m . pt . 86 - 88 ° c . ir vmax ( kbr ): 3327 . 8 ( n ═ c ), 2929 . 3 ( c — h stretching ), 1751 . 8 and 1710 . 7 ( c ═ o ), 1628 . 0 ( c ═ c stretching ), 1249 . 0 and 1194 . 1 ( c ( o ) or aromatic ), 1082 . 8 ( c — o — c ) cm − 1 . hrms : requires : 436 . 1008 ( m + + 23 ), found : 436 . 1004 ( m + + 23 ). 1 h nmr δ ( cdcl 3 ): 2 . 37 ( 3h , s , ococh 3 ), 4 . 09 ( 5h , m , is1 - h 2 [ α + β ] and is6 - h 2 [ α + β ]), 4 . 65 ( 1h , d , j 4 . 52 hz , ish - 3 ), 5 . 05 ( 1h , t , j 5 . 52 and 5 . 04 hz , ish - 4 ), 5 . 46 ( 2h , dd , j 5 . 52 and 5 . 04 hz , ish - 5 and ish - 2 ), 7 . 12 ( 1h , d , j 7 . 04 hz , ar 1 h - 2 ), 7 . 33 ( 1h , m , ar 1 h - 3 ), 7 . 59 ( 2h , t , j 6 . 04 and 6 . 04 hz , ar 1 h - 5 and ar 1 h - 4 ), 7 . 90 ( 1h , d , j 5 . 04 hz , ar 2 h - 6 ), 8 . 01 ( h , dd , j 2 . 0 and 1 . 52 hz , ar 2 h - 2 ), 8 . 84 ( 1h , s , ar 2 h - 5 ), 8 . 98 ( 1h , s , ar 2 h - 3 ). to a solution of isosorbide - 2 - aspirinate 17 ( 0 . 27 g , 0 . 87 mmol ) in dichloromethane ( 20 ml ) was added benzyloxy benzoic acid ( 0 . 20 g , 0 . 87 mmol ), dcc ( 0 . 18 g , 0 . 87 mmol ) and dmap ( 0 . 01 g , 0 . 09 mmol ). the reaction vessel was stirred at room temperature for 24 hours before filtering and washing the filtrate with hcl ( 30 ml , 0 . 1 m ), saturated aqueous nahco 3 ( 30 ml ) and water ( 2 × 30 ml ). after drying over anhydrous na 2 so 4 , the dichloromethane was removed in vacuo to give 0 . 7 g of crude product as colourless oil . purification by column chromatography over silica gel using hexane and ethyl acetate ( 3 : 1 ) as eluant yielded 0 . 19 g of compound 9 as white crystals ( 41 . 5 %): m . pt . 76 - 78 ° c . ir vmax ( kbr ): 1772 . 7 and 1726 . 2 ( c ═ o ), 1276 . 6 ( c ( o ) or aromatic ), 1078 . 1 ( c — o — c ) cm − 1 . hrms : requires : 541 . 1475 ( m + + 23 ), found : 541 . 1460 ( m + + 23 ). 1 h nmr δ ( cdcl 3 ): 2 . 05 ( 2h , s , aroch 2 ar ), 2 . 36 ( 3h , s , ococh 3 ), 3 . 92 ( 1h , q , j 5 . 0 , 5 . 04 and 5 . 0 hz , is6α - h ), 4 . 02 ( 3h , m , is1h [ α + β ]), 4 . 13 ( 1h , q , j 7 . 04 , 7 . 0 and 7 . 56 hz , is6h - β ), 4 . 62 ( 1h , d , j 5 . 0 hz , ish - 3 ), 5 . 02 ( 1h , t , j 5 . 04 and 5 . 0 hz , ish - 4 ), 5 . 19 ( 2h , s , ish - 5 ), 5 . 39 ( 2h , m , ish - 5 ), 7 . 03 ( 2h , m , 2 × ar — h ) 7 . 11 ( 1h , d , j 7 . 56 hz , ar — h ) 7 . 33 ( 2h , m , ar — h ), 7 . 41 ( 2h , t , j 6 . 04 and 7 . 04 hz , ar — h ), 7 . 48 ( 3h , m , ar — h ) 7 . 58 ( 1h , m , ar — h ), 7 . 92 ( 1h , dd , j 1 . 52 and 2 . 0 hz , ar — h ) 8 . 01 ( 1h , dd , j 1 . 48 and 2 . 0 hz , ar — h ). 13 c nmr ppm ( cdcl 3 ): 20 . 49 ( oco c h 3 ), 70 . 12 ( isc - 6 ), 70 . 19 ( isc - 2 ), 72 . 59 ( isc - 5 ), 73 . 84 ( isc - 3 ), 78 . 28 ( aro c h 2 ), 80 . 48 ( isc - 1 ), 85 . 59 ( isc - 4 ), 113 . 18 ( ar 2 c - 5 ), 119 . 29 ( ar 2 c - 1 ). 120 . 10 ( ar 2 c - 3 ), 122 . 30 ( ar 1 c - 5 ), 123 . 41 ( ar 1 c - 1 ), 125 . 64 ( ar 1 c - 3 ), 126 . 78 ( ar 3 c - 2 and ar 3 c - 6 ), 127 . 51 ( ar 3 c - 4 ), 128 . 08 ( ar 3 c - 3 and ar 3 c - 6 ), 128 . 13 ( ar 1 c - 2 ), 131 . 44 ( ar 2 c - 2 ), 131 . 81 ( ar 1 c - 4 ) 133 . 44 ( ar 2 c - 4 ), 136 . 09 ( ar 3 c - 1 ), 150 . 21 ( ar 1 c - 6 ), 157 . 95 ( ar 2 c - 6 ), 163 . 16 ( aro c ( o ) me ), 165 . 20 ( ar c ( o ) or ), 169 . 28 ( ar c ( o ) or ). isosorbide - 2 - aspirinate 17 ( 0 . 69 g , 2 . 2 mmol ) was dissolved in dcm ( 20 mls ) to which was added dcc ( 0 . 44 g , 2 . 2 mmol ) and dmap ( 0 . 05 g , 0 . 22 mmol ) and the reaction vessel was stirred at 0 ° c . for 10 minutes . after returning to room temperature , anthranillic acid ( 0 . 29 g , 2 . 2 mmol ) was added allowed to stir for 3 hours . the reaction mixture was washed with hcl ( 20 ml , 1m ), saturated aqueous nahco 3 ( 20 ml ), saturated brine solution ( 20 ml ) and water ( 2 × 20 ml ), dried over anhydrous na 2 so 4 and solvent removed in vacuo to yield product as crude yellow oil . purification by column chromatography over silica gel using hexane and ethyl acetate ( 4 : 1 ) as eluant yielded compound 10 as a yellow solid ( 0 . 39 g , 41 . 5 %). product was stored at 0 - 4 ° c . until required for testing . m . pt . 150 - 152 ° c . ir vmax ( kbr ): 3443 . 4 ( n — h stretching ), 2920 . 5 ( c — h stretching ), 1742 . 7 ( c ═ o ), 1548 . 0 ( n — h bending ), 1220 . 9 and 1158 . 6 ( c ( o ) or , aromatic ), 1047 . 4 ( c — o — c ) cm − 1 . 1 h nmr δ ( cdcl 3 ): 2 . 07 ( 3h , s , ococh 3 ), 4 . 04 ( 2h , m , nh 2 ), 3 . 88 ( 1h , q , j 5 . 52 , 4 . 52 and 5 . 0 hz , ish - 1 ), 4 . 16 ( 2h , m , ish - 2 and ish - 5 ), 4 . 69 ( 2h , dd , j 4 . 52 and 4 . 52 , ish - 1 and ish - 3 ), 4 . 95 ( 1h , t , j 5 . 04 and 5 . 0 hz , ish - 4 ), 6 . 69 ( 1h , t , j 57 . 52 and 7 . 52 hz , ar 2 h - 5 ), 6 . 91 ( 1h , t , j 8 . 0 and 7 . 04 , ar 2 h - 3 ), 7 . 01 ( 2h , d , j 8 . 52 , ar 1 h - 3 and ar 1 h - 5 ), 7 . 31 ( 1h , m , ar 2 h - 4 ), 7 . 51 ( 1h , m , ar 1 h - 4 ), 7 . 82 ( 1h , dd , j 2 . 0 and 2 . 0 hz , ar 2 h - 2 ), 7 . 92 ( 1h , d , j 7 . 04 , ar 1 h - 2 ). 13 c nmr ppm ( cdcl 3 ): 20 . 13 ( aroco c h 3 ), 69 . 82 ( isc - 1 ), 70 . 02 ( isc - 5 ), 75 . 01 ( isc - 2 ), 75 . 03 ( isc - 6 ), 79 . 29 ( isc - 3 ), 81 . 86 ( isc - 4 ), 115 . 02 ( ar 2 c - 5 ), 117 . 49 ( ar2c - 1 ), 119 . 32 ( ar 2 c - 3 ), 121 . 63 ( ar 1 c - 5 ), 123 . 59 ( ar 1 c - 1 ), 125 . 42 ( ar 1 c - 3 ), 130 . 23 ( ar 1 c - 2 ), 130 . 59 ( ar 2 c - 2 ), 133 . 27 ( ar 1 c - 4 ), 133 . 36 ( ar 2 c - 4 ), 147 . 99 ( ar 2 c - 6 ), 154 . 32 ( ar 1 c - 6 ), 167 . 02 ( o c oar ), 167 . 06 ( o c oar ), 168 . 92 ( o c och 3 ). isosorbide - 2 - aspirinate 17 ( 0 . 2 g , 0 . 65 mmol ) was dissolved in toluene ( 15 ml ) at 0 ° c . to which was added dmap ( 0 . 08 g , 0 . 65 mmol ) and dcc ( 0 . 13 g , 0 . 65 mmol ). after 10 mins the reaction vessel was returned to room temperature , 2 - anisic acid ( 2 - methoxybenzoic acid , 0 . 10 g , 0 . 65 mmol ) was added and allowed to stir for 12 hours . the reaction mixture was washed with hcl ( 20 ml , 1m ), saturated aqueous nahco 3 ( 20 ml ), saturated brine solution ( 20 ml ) and water ( 3 × 20 ml ), dried over anhydrous na 2 so 4 and solvent removed in vacuo to yield product as a crude oil . purification by column chromatography over silica gel using hexane and ethyl acetate ( 3 : 1 ) as eluant yielded compound 11 as white crystals ( 0 . 23 g , 79 . 8 %): m . pt . 132 - 134 ° c . ir vmax ( kbr ): 2920 . 5 ( c — h stretching ), 1764 . 9 and 1720 . 4 ( c ═ o ), 1253 . 2 ( c ( o ) or , aromatic ), 1075 . 2 ( c — o — c ) cm − 1 . hrms : requires : 465 . 1162 ( m + + 23 ), found : 465 . 1131 ( m + + 23 ), 1 h nmr δ ( cdcl 3 ): 2 . 89 ( 3h , s , ococh 3 ) 3 . 95 ( 3h , m , aroch 3 , 4 . 06 ( 1h , m , is6 - hα ), 4 . 14 ( 3h , m , is1 - h 2 [ α + β ] and is6 - hβ ), 4 . 64 ( 1h , d , j 5 . 0 hz , ish - 3 ), 5 . 03 ( 1h , t , j 5 . 04 and 5 . 52 hz , ish - 4 ), 5 . 40 ( 1h , t , j 5 . 0 and 5 . 52 hz , ish - 5 ), 5 . 45 ( 1h , d , j 2 . 0 hz , ish - 2 ), 7 . 01 ( 2h , q , j 4 . 52 , 2 . 52 and 6 . 0 hz , ar 2 h - 3 and ar 2 h - 5 ), 7 . 11 ( 1h , d , j 8 . 04 hz , ar 1 h - 2 ), 7 . 31 ( 1h , m , ar 1 h - 3 ), 7 . 50 ( 1h , m , ar 1 h - 4 ), 7 . 58 ( 1h , m , ar 1 h - 5 ), 7 . 88 ( 1h , dd , j 2 . 04 and 1 . 52 hz , ar 2 h - 4 ), 8 . 01 ( 1h , dd , j 1 . 52 and 1 . 48 hz , ar 2 h - 6 ). 13 c nmr ppm ( cdcl 3 ): 20 . 42 ( aroco c h 3 ), 55 . 52 ( aro c h 3 ), 70 . 41 ( isc - 1 ), 72 . 66 ( isc - 6 ), 73 . 69 ( iso c oar ), 76 . 58 ( isc - 5 ). 78 . 25 ( isc - 4 ), 80 . 56 ( isc - 2 ), 85 . 64 ( isc - 3 ), 111 . 74 ( ar 2 c - 3 ) 118 . 83 ( ar 2 c - 1 ), 122 . 39 ( ar 2 c - 5 ), 122 . 91 ( ar 1 c - 5 ), 123 . 38 ( ar 1 c - 1 ), 125 . 42 ( ar 1 c - 3 ), 125 . 56 ( ar 1 c - 2 ), 131 . 38 ( ar 2 c - 6 ), 133 . 45 ( ar 1 c - 4 ), 133 . 75 ( ar 2 c - 4 ), 150 . 24 ( ar 1 c - 6 ), 159 . 09 ( ar 2 c - 6 ), 164 . 79 ( ar c oor ), 169 . 13 ( aro c ( o ) ch 3 ). isosorbide - 2 - aspirinate 17 ( 0 . 2 g , 0 . 65 mmol ) was dissolved in toluene ( 15 ml ) at 0 ° c . to which was added dmap ( 0 . 08 g , 0 . 65 mmol ) and dcc ( 0 . 13 g , 0 . 65 mmol ). after 10 mins the reaction vessel was returned to room temperature , 3 - anisic acid ( 3 - methoxybenzoic acid ) ( 0 . 10 g , 0 . 65 mmol was added and allowed to stir for 12 hours . the reaction mixture was washed with hcl ( 20 ml , 1m ), saturated aqueous nahco 3 ( 20 ml ), saturated brine solution ( 20 ml ) and water ( 3 × 20 ml ), dried over anhydrous na 2 so 4 and solvent removed in vacuo to yield product as a crude oil . purification by column chromatography over silica gel using hexane and ethyl acetate ( 3 : 1 ) as eluant yielded compound 12 as white crystals ( 0 . 23 g , 79 . 8 %): m . pt . 125 - 128 ° c . ir vmax ( kbr ): 2980 . 9 ( c — h stretching ), 1768 . 3 and 1723 . 8 ( c ═ o ), 1298 . 5 and 1253 . 5 ( c ( o ) or , aromatic ), 1075 . 9 ( c — o — c ) cm − 1 . hrms : requires : 465 . 1162 ( m + + 23 ), found : 465 . 1168 ( m + + 23 ), 1 h nmr δ ( cdcl 3 ): 2 . 36 ( 3h , s , ococh 3 ) 3 . 87 ( 3h , s , aroch 3 ), 4 . 05 ( 1h , d , j 5 . 0 hz , is6 - hα ), 4 . 09 ( 2h , t , j 3 . 0 and 2 . 52 hz , is1 - h 2 [ α + β ]), 4 . 14 ( 2h , d , j 7 . 52 hz , is6 - hβ ), 4 . 64 ( 1h , d , j 5 . 04 hz , ish - 3 ), 5 . 03 ( 1h , t , j 5 . 04 and 5 . 52 hz , ish - 4 ), 5 . 43 ( 1h , q , j 5 . 0 , 5 . 52 and 5 . 52 hz , ish - 5 ), 5 . 47 ( 1h , s , ish - 2 ), 7 . 13 ( 2h , q , j 4 . 52 , 2 . 52 and 6 . 0 hz , ar 2 h - 3 and ar 2 h - 5 ), 7 . 33 ( 2h , m , ar 1 h - 2 and ar 1 h - 3 ), 7 . 58 ( 2h , m , ar 1 h - 4 and ar 1 h - 5 ), 7 . 69 ( 1h , d , j 7 . 52 hz , ar 2 h - 4 ), 8 . 01 ( 1h , dd , j 1 . 52 and 1 . 52 hz , ar 2 h - 6 ). 13 c nmr ppm ( cdcl 3 ): 20 . 41 ( aroco c h 3 ), 54 . 99 ( aro c h 3 ), 70 . 43 ( isc - 1 ), 72 . 74 ( isc - 6 ), 74 . 05 ( iso c oar ), 76 . 58 ( isc - 5 ), 78 . 17 ( isc - 4 ), 80 . 49 ( isc - 2 ), 85 . 67 ( isc - 3 ), 113 . 96 ( ar 2 c - 2 ), 119 . 21 ( ar 2 c - 4 ), 121 . 67 ( ar 1 c - 5 ), 122 . 34 ( ar 2 c - 6 ), 123 . 38 ( ar 1 c - 1 ), 125 . 56 ( ar 1 c - 3 ), 129 . 03 ( ar 2 c - 5 ), 130 . 39 ( ar 1 c - 2 ), 131 . 36 ( ar 2 c - 1 ), 133 . 77 ( ar 1 c - 4 ), 150 . 24 ( ar 1 c - 6 ), 159 . 20 ( ar 2 c - 3 ), 163 . 14 ( ar c oor ), 169 . 11 ( arococh 3 ). isosorbide - 2 - aspirinate 17 ( 0 . 2 g , 0 . 65 mmol ) was dissolved in toluene ( 15 ml ) at 0 ° c . to which was added dmap ( 0 . 08 g , 0 . 65 mmol ) and dcc ( 0 . 13 g , 0 . 65 mmol ). after 10 mins the reaction vessel was returned to room temperature , 4 - anisic acid ( 4 - methoxybenzoic acid ) ( 0 . 10 g , 0 . 65 mmol was added and allowed to stir for 12 hours . the reaction mixture was washed with hcl ( 20 ml , 1m ), saturated aqueous nahco 3 ( 20 ml ), saturated brine solution ( 20 ml ) and water ( 3 × 20 ml ), dried over anhydrous na 2 so 4 and solvent removed in vacuo to yield product as a crude oil . purification by column chromatography over silica gel using hexane and ethyl acetate ( 2 : 1 ) as eluant yielded product as white crystals ( 0 . 17 g , 58 . 9 %): m . pt . 141 - 144 ° c . ir vmax ( kbr ): 2994 . 1 and 2936 . 7 ( c — h stretching ), 1764 . and 724 . 9 ( c ═)), 1605 . 8 ( c ═ c stretching ), 1260 . 5 ( c ( o ) or , aromatic ), 1078 . 6 ( c — o — c ) cm − 1 . hrms : requires : 465 . 1162 ( m + + 23 ), found : 465 . 1157 ( m + + 23 ). 1 h nmr δ ( cdcl 3 ): 2 . 32 ( 3h , s , ococh 3 ), 3 . 84 ( 3h , s , aroch 3 , 3 . 99 ( 1h , m , is6 - hα ), 4 . 07 ( 6h , m , is1 - h 2 [ α + β ] and is6 - hβ ), 4 . 59 ( 1h , d , j 4 . 52 hz , ish - 3 ), 4 . 98 ( 1h , t , j 5 . 52 and 5 . 0 hz , ish - 4 ), 5 . 38 ( 1h , t , j 5 . 0 and 5 . 52 hz , ish - 5 ), 5 . 43 ( 1h , d , j 2 . 0 hz , ish - 2 ), 6 . 91 ( 2h , d , j 8 . 52 hz , ar 2 h - 3 and ar 2 h - 5 ), 7 . 08 ( 1h , d , j 8 . 0 hz , ar 1 h - 4 ), 7 . 28 ( 1h , t , j 7 . 56 and 9 . 52 hz , ar 1 h - 2 ), 7 . 54 ( 1h , t , j 8 . 0 and 7 . 52 hz , ar 1 h - 3 ), 7 . 99 ( 3h , q , j 9 . 0 , 7 . 04 and 8 . 04 hz , ar 1 h - 1 , ar 2 h - 2 and ar 2 h - 6 ). 13 c nmr ppm ( cdcl 3 ): 20 . 48 ( aroco c h 3 ), 59 . 83 ( aro c h 3 ), 70 . 41 ( isc - 1 ), 72 . 82 ( isc - 6 ), 73 . 58 ( iso c oar ), 76 . 58 ( isc - 5 ). 78 . 26 ( isc - 4 ), 80 . 47 ( isc - 2 ), 85 . 46 ( isc - 3 ), 113 . 33 ( ar 2 c - 3 and ar 2 c - 5 ), 121 . 46 ( ar 1 c - 5 ), 122 . 35 ( ar 2 c - 1 ), 123 . 36 ( ar 1 c - 1 ), 125 . 54 ( ar 1 c - 3 ), 131 . 35 ( ar 1 c - 2 ), 133 . 73 ( ar 2 c - 2 and ar 2 c - 6 ), 133 . 76 ( ar 1 c - 4 ), 150 . 23 ( ar 1 c - 6 ), 163 . 12 ( aro c h 3 and ar 2 c - 4 ), 165 . 09 ( ar c oor ), 169 . 08 ( ar c oor ), 170 . 52 ( aro c och 3 ). a solution of isosorbide - 2 - aspirinate 17 ( 0 . 2 g , 0 . 65 mmol ) was dissolved in toluene at 0 ° c . to which was added triethylamine ( 0 . 13 mls , 0 . 98 mmol ) and 4 - toluoyl chloride ( 0 . 93 ml , 0 . 78 mmol ). the reaction vessel was returned to room temperature and allowed to stir for 10 hours , then washed with hcl ( 30 ml , 1m ), saturated aqueous nahco 3 ( 30 ml ), water ( 3 × 30 ml ) and saturated nacl solution ( 30 ml ). the reaction was dried with anhydrous na 2 so 4 and solvent was removed in vacuo using ethyl acetate as co - solvent to give crude product . purification by column chromatography using hexane and ethyl acetate ( 9 : 1 ) as eluant gave compound 14 as white crystals ( 0 . 1 g , 35 . 99 %): m . pt . 102 - 104 ° c . ir vmax ( kbr ): 2982 . 7 and 2923 . 6 ( c — h stretching ), 1763 . 9 and 1717 . 8 ( c ═ o ), 1608 . 5 ( c ═ c ), 1275 . 4 and 1202 . 0 ( c ( o ) or ), 1100 . 3 ( c — o — c )) cm − 1 . hrms : requires : 449 . 1212 ( m + + 23 ), found : 449 . 1229 ( m + + 23 ), 1 h nmr δ ( cdcl 3 ): 2 . 19 ( 3h , s , ococh 3 ), 2 . 43 ( 3h , s , ar — ch 3 ), 4 . 05 ( 2h , d , j 5 . 0 hz , is1h 2 [ α +] and is6h 2 [ α +]), 4 . 09 ( 2h , t , j 4 . 04 and 3 . 52 hz , ish - 6 ), 4 . 14 ( 1h , t , j 7 . 04 and 7 . 52 hz , ish - 5 ), 4 . 63 ( 1h , d , j 5 . 0 hz , ish - 3 ), 5 . 03 ( 1h , t , j 4 . 8 and 5 . 0 , ish - 4 ), 5 . 44 ( 2h , m , ish - 2 ), 7 . 11 ( 1h , d , j 8 . 04 hz , ar — h ), 7 . 27 ( 2h , d , j 8 . 56 hz , ar — h ), 7 . 33 ( 1h , t , j 7 . 52 and 7 . 52 hz , ar — h ), 7 . 55 ( 1h , t , j 1 . 52 and 6 . 04 hz , ar — h ), 8 . 00 ( 3h , m , ar — h ). 13 c nmr ppm ( cdcl 3 ): 13 . 71 ( arch 3 ), 20 . 54 ( ococh 3 ), 70 . 49 ( isc - 1 ), 72 . 75 ( isc - 6 ), 73 . 78 ( isc - 5 ), 78 . 13 ( isc - 4 ), 80 . 72 ( isc - 2 ), 85 . 62 ( isc - 3 ), 122 . 25 ( ar 1 c - 1 ), 123 . 38 ( ar 1 c - 4 ), 125 . 64 ( ar 1 c - 6 ), 126 . 26 ( ar 1 c - 2 and ar 2 c - 4 ), 128 . 74 ( ar 2 c - 2 and ar 2 c - 5 ), 129 . 36 ( ar 2 c - 6 ), 131 . 42 ( ar 2 c - 3 ), 133 . 87 ( ar 1 c - 3 ), 143 . 62 ( ar 2 c - 1 ), 150 . 22 ( ar 1 c - 5 ), 163 . 15 ( aro c och 3 ), 165 . 48 ( is — o c oar ), 169 . 27 ( ar c oo ). ( please note a compound 16 is not included in this description ) isosorbide - 2 - aspirinate 17 ( 0 . 2 g , 0 . 65 mmol ) was dissolved in dcm ( 10 mls ) at room temperature . to the reaction vessel was added 4 - nitrobenzoylchloride ( 0 . 15 g , 0 . 78 mmol ) and triethylamine ( 1 . 12 ml , 0 . 78 mmol ). the reaction was allowed to stir at room temperature for 48 hours before washing with hcl ( 20 ml , 1m ), saturated aqueous nahco 3 ( 25 ml ), saturated brine solution ( 20 ml ) and water ( 2 × 20 ml ), dried over anhydrous na 2 so 4 and solvent removed in vacuo to yield product as a crude yellow oil . purification by column chromatography over silica gel using hexane and ethyl acetate ( 3 : 2 ) as eluant yielded compound 15 as a colourless oil which when recrystallised in ethanol afforded product as white crystals ( 0 . 15 g , 50 . 5 %). m . pt . 66 - 68 ° c . ir vmax ( kbr ): 1772 . 7 and 1726 . 2 ( c ═ o ), 1276 . 6 ( c ( o ) or , aromatic ), 1078 . 1 ( c — o — c ) cm − 1 . hrms : requires : 480 . 0907 ( m + + 23 ), found : 480 . 0922 ( m + + 23 ), 1 h nmr δ ( cdcl 3 ): 2 . 34 ( 3h , s , ococh 3 ), 4 . 07 ( 4h , m , ish - 3 ), 4 . 64 ( 1h , d , j 4 . 52 hz , ish - 1 and ish - 4 ), 5 . 04 ( 1h , t , j 5 . 04 and 5 . 0 hz , ish - 5 ), 5 . 45 ( 2h , m , ish - 2 and ish - 6 ), 7 . 10 ( 1h , dd , j 1 . 0 and 1 . 0 hz , ar 1 h - 2 ), 7 . 31 ( 1h , m , ar 1 h - 3 ), 7 . 53 ( 1h , m , ar 1 h - 4 ), 7 . 99 ( 1h , dd , j 2 . 04 and 1 . 52 hz , ar 1 h - 5 ), 8 . 25 ( 4h , dd , j 2 . 0 and 2 . 04 hz , ar 2 h - 2 and ar 2 h - 6 ), 8 . 31 ( 2h , dd , j 2 . 0 and 2 . 04 hz , ar 2 h - 3 and ar 2 h - 5 ). 13 c nmr ppm ( cdcl 3 ): 20 . 41 ( aroco c h 3 ), 70 . 26 ( isc - 1 ), 72 . 76 ( isc - 5 ), 74 . 88 ( isc - 2 and isc - 6 ), 80 . 52 ( isc - 4 ), 85 . 68 ( isc - 3 ), 123 . 16 ( ar 1 c - 5 ), 123 . 36 ( ar 1 c - 1 ), 125 . 58 ( ar 2 c - 3 and ar 2 c - 5 ), 130 . 39 ( ar 1 c - 2 ), 131 . 32 ( ar 2 c - 2 and ar 2 c - 6 ), 133 . 87 ( ar 1 c - 4 ), 150 . 32 ( ar 2 c - 4 ), 163 . 07 ( o c oar ), 163 . 53 ( o c oar ), 169 . 09 ( o c och 3 ). a stirred solution of acetylsalicyloyl chloride ( m . w . 198 . 60 g / mol , 10 . 9 g = 54 . 9 mmol ) in dichloromethane ( 160 ml ) was treated with triethylamine ( m . w . 101 . 19 g / mol , d = 0 . 726 g / ml , 9 . 1 ml = 65 . 4 mmol ). the mixture was cooled to 0 ° c . and 5 - ismn ( m . w . 191 . 12 g / mol , 10 g = 52 . 3 mmol ) was added . the flask was stirred at room temperature overnight and protected from light . mixture was washed with hcl ( 2 m ), 5 % nahco 3 and water , dried over sodium sulfate and concentrated to an oil . this was recrystallised using hot ethanol ( crystallization can be quite slow ) to give 10 g of yellow crystals . this was dissolved in methanol / ethyl acetate ( 1 : 1 ), pd / c was added and a hydrogen balloon was attached . stirred overnight and monitored by tlc ( hexane / ethyl acetate 2 : 1 ) to determine reaction completion . mixture was filtered and the solvent removed . some dichloromethane added and concentrated , diethyl ether added , allowed to stand for 10 - 15 mins and concentrated to white crystals ( 7 . 4 g ). 1 h nmr δ ( cdcl 3 ) 400 mhz : 2 . 37 ( 3h , s , ococ h 3 ), 3 . 6 ( 1h , m , ish - 6 ), 3 . 9 ( 1h , m ish - 6 ′), 4 . 07 ( 2h , 2 × dd , ish - 1 / h - 1 ′), 4 . 3 ( 1h , q , ish - 3 ), 4 . 58 ( 1h , d , ish - 4 ), 4 . 69 ( 1h , m , ish - 2 ), 5 . 45 ( 1h , d , ish - 5 ), 7 . 11 ( 1h , d , ar — h ), 7 . 28 ( 1h , t , ar — h ), 7 . 57 ( 1h , t , ar — h ), 8 . 00 ( 1h , dd , ar — h ). 13 c nmr ppm ( cdcl 3 ) 400 mhz : 20 . 48 ( oco c h 3 ), 71 . 56 ( isc - 1 ), 72 . 91 ( isc - 6 ), 73 . 11 ( isc - 5 ), 78 . 44 ( isc - 2 ), 81 . 56 ( isc - 4 ), 85 . 09 ( isc - 3 ), 122 . 18 ( ar 2 c - 2 / c - 6 ), 123 . 42 , 125 . 66 ( ar 2 c - 4 ), 131 . 37 ( ar 1 c - 4 ), 133 . 95 , 150 . 23 ( ar 2 o c o ), 163 . 03 ( o c oarch 2 ono 2 ), 169 . 27 ( ar c ( o ) or ). to a solution of isosorbide - 2 - aspirinate - 5 - salicylate ( 0 . 15 g , 0 . 35 mmol ) and dbu ( 0 . 052 ml , 0 . 35 mmol ) in dichloromethane ( 5 ml ) was added bromoacetyl chloride ( 0 . 03 ml , 0 . 35 mmol ) and the reaction mixture was allowed to stir overnight . the reaction was washed with water ( 2 × 5 ml ) and the solvents removed in vacuo to yield compound 18 as a colourless oil ( 0 . 13 g ). ir vmax ( film ) cm − 1 : 1765 . 6 and 1724 . 3 ( c ═ o ), 1608 . 1 ( c ═ o ), 1288 . 4 and 1251 . 4 ( c ( o ) or ), 1196 . 9 and 1135 . 6 ( c — o — c ), 732 . 6 ( c — br ). hrms : requires : 531 . 1013 ( m + ); found : 570 . 4453 ( m + + 23 ). δh ( 400 mhz ; cdcl 3 ): 2 . 37 ( 3h , s , ococh 3 ), 4 . 07 ( 4h , m , is1 , 6 - h ), 4 . 48 ( 2h , s , ch 2 ), − 4 . 63 ( 1h , m , is4 - h ), 4 . 98 ( 1h , m , is3 - h ), 5 . 40 ( 2h , m , is2 , 5 - h ), 7 . 11 ( 1h , d , j8 . 0 and 7 . 5 hz , ar — h ), 7 . 60 ( 2h , m , 2 × arh ), 8 . 11 ( 1h , d , j1 . 5 hz , ar — h ), 8 . 12 ( 1h , d , j 1 . 5 hz , ar — h ); δ 13 c ( 100 mhz ; cdcl 3 ): 20 . 86 ( ococh 3 ), 40 . 99 ( ch2 ), 70 . 47 ( is — c ), 73 . 24 ( is6 - c ), 74 . 69 ( is4 - c ), 78 . 40 ( is3 - c ), 81 . 09 ( is5 - c ), 86 . 07 ( is2 - c ), 123 . 61 , 123 . 83 , 126 . 01 , 126 . 65 and 131 . 78 , 132 . 21 , 134 . 26 , 134 . 42 , 150 . 23 , 150 . 69 , 163 . 5 , 166 . 11 , 169 . 55 . cycolpropane carbonyl chloride ( m . w . 104 . 54 g / mol , d = 1 . 152 g / ml , 250 μl = 2 mmol ) was dissolved in dcm ( 10 ml ). triethylamine ( 500 μl = 6 mmol ) was added and the mixture was cooled to 0 ° c . isosorbide - 2 - aspirinate , 17 was added ( 506 . 2 mg = 1 . 6 mmol ) and the reaction was stirred overnight at room temperature . washed with 2 m hcl ( 10 ml ), 5 % nahco 3 ( 10 ml ) and water ( 10 ml ). dried over sodium sulfate and concentrated . purified by column chromatography ( hexane / ethyl acetate 2 : 1 ) rf = 0 . 3 to give 396 mg of an oil . 1 h nmr δ ( cdcl 3 ) 400 mhz : 0 . 9 - 1 . 18 ( 2 × dd and t , 4h , 2 × c h 2 ), 2 . 32 ( 3h , s , ococ h 3 ), 3 . 78 ( m , 1h , ish - 1 ), 3 . 9 ( m , 1h , ish - 6 ), 4 . 06 ( 2h , d , ish - 1 ′ and ish - 6 ′), 4 . 5 ( 1h , d , ish - 3 ), 4 . 83 ( 1h , t , ish - 4 ), 5 . 12 ( 1h , q , ish - 2 ), 5 . 38 ( 1h , s , h - 5 ), 7 . 06 ( 1h , d , ar — h ), 7 . 26 ( 1h , t , ar — h ), 7 . 52 ( 1h , t , ar — h ), 7 . 95 ( 1h , d , ar — h ). 13 c nmr ppm ( cdcl 3 ) 400 mhz : 9 and 10 ( 2 × c h 2 ), 12 . 15 ( c h ), 20 . 43 ( oco c h 3 ), 69 . 96 ( isc - 1 ), 72 . 71 ( isc - 6 ), 73 . 40 ( isc - 5 ), 78 . 14 ( isc - 2 ), 80 . 39 ( isc - 4 ), 85 . 35 ( isc - 3 ), 122 . 20 ( arc - 6 ), 123 . 37 ( arc - 2 ), 125 . 59 ( arc - 4 ), 131 . 36 ( arc - 3 ), 133 . 86 ( arc - 5 ), 150 . 19 ( arc - 1 ), 163 . 05 ( ar 2 o c o ), 169 . 18 ( ch 3 o c oar ), 173 . 78 ( o c ocyclopropane ). isosorbide - 2 - aspirinate 17 ( 200 mg , 0 . 6 mmol ) and 4 - cyanobenzoylchloride ( 120 mg , 0 . 72 mmol ) were reacted together according to gp2 to give 213 mg ( 81 %) of a yellow oil after flash chromatography with etoac : hex 1 : 4 . 1 h nmr ( cdcl 3 , 400 mhz ) δ 8 . 2 ( 2h , d , j = 8 . 5 hz ), 8 . 0 ( 1h , dd , j = 8 hz , 1 . 5 hz ), 7 . 8 ( 2h , d , j = 10 hz ), 7 . 6 ( 1h , dt , j = 8 hz , 1 . 5 hz ), 7 . 35 ( 1h , dt , j = 6 . 5 hz , 1 hz ), 7 . 1 ( 1h , d , j = 8 . 5 hz ), 5 . 45 ( 2h , m ), 5 . 05 ( 1h , t , j = 5 hz ), 4 . 65 ( 1h , d , j = 5 hz ), 4 . 1 ( 4h , m ), 2 . 4 ( 3h , s ). 13 c nmr ( cdcl 3 400 mhz ) δ 169 . 3 , 163 . 8 , 163 . 1 , 150 . 3 , 133 . 9 , 132 . 8 , 131 . 9 , 131 . 4 , 129 . 8 , 125 . 7 , 123 . 4 , 122 . 1 , 117 . 4 , 116 . 3 , 85 . 7 , 80 . 7 , 80 . 5 , 77 . 9 , 76 . 8 74 . 8 , 72 . 7 , 70 . 3 , 20 . 5 . hrms ( ei ) c 23 h 19 o 8 n , [ m + h ] + requires 438 . 4068 , found 438 . 4183 . anal . c 23 h 19 o 8 n requires c , 63 . 16 ; h , 4 . 38 ; n , 3 . 20 . found c , 63 . 46 ; h , 4 . 51 ; n , 2 . 97 . isosorbide - 2 - aspirinate 17 ( 200 mg , 0 . 6 mmol ) and 4 - phenylbenzoylchloride ( 156 mg , 0 . 72 mmol ) were reacted together to give 185 mg ( 65 %) of a colourless oil after flash chromatography with etoac : hex 1 : 4 . 1 h nmr ( cdcl 3 , 400 mhz ) δ 8 . 2 ( 2h , d , j = 8 . 5 hz ), 8 . 0 ( 1h , dd , j = 8 hz , 1 . 5 hz ), 7 . 7 ( 2h , d , j = 8 . 5 hz ), 7 . 65 ( 2h , d , j = 7 hz ), 7 . 6 ( 1h , dt , j = 8 hz , 1 . 5 hz ), 7 . 5 ( 2h , t , j = 7 . 5 hz ), 7 . 45 ( 1h , t , j = 8 hz ), 7 . 35 ( 1h , dt , j = 6 . 5 hz , 1 hz ), 7 . 1 ( 1h , d , j = 8 . 5 hz ), 5 . 45 ( 2h , m ), 5 . 05 ( 1h , t , j = 5 hz ), 4 . 65 ( 1h , d , j = 5 hz ), 4 . 1 ( 4h , m ), 2 . 4 ( 3h , s ). 13 c nmr ( cdcl 3 400 mhz ) δ 169 . 3 , 165 . 3 , 163 . 1 , 150 . 3 , 145 . 6 , 139 . 5 , 133 . 9 , 131 . 4 , 129 . 8 , 128 . 5 , 127 . 8 , 127 . 7 , 126 . 8 , 126 . 7 125 . 7 , 123 . 4 , 122 . 1 , 85 . 7 , 80 . 7 , 78 . 12 , 77 . 2 , 76 . 8 73 . 9 , 72 . 7 , 70 . 5 , 20 . 5 . hrms ( ei ) c 28 h 24 o 8 , [ m + h ] + requires 489 . 4933 , found 489 . 5021 . anal . c 28 h 24 o 8 requires c , 68 . 85 ; h , 4 . 95 . found c , 68 . 88 ; h , 5 . 08 . isosorbide - 2 - aspirinate 17 ( 250 mg , 0 . 8 mmol ) and 6 - chloronicotinoylchloride ( 230 mg , 0 . 9 mmol ) were reacted together according to gp2 to give 256 mg ( 70 %) of a white solid after flash chromatography with etoac : hex 3 : 7 . 1 h nmr ( cdcl 3 , 400 mhz ) δ 9 . 3 ( 1h s ) 8 . 9 ( 1h , s ), 8 . 3 ( 2h , d , j = 8 . 5 hz ), 8 . 0 ( 1h , dd , j = 8 hz , 1 . 5 hz ), 7 . 6 ( 1h , dt , j = 8 hz , 1 . 5 hz ), 7 . 45 ( 1h , t , j = 1 hz ) 7 . 35 ( 1h , dt , j = 6 . 5 hz , 1 hz ), 7 . 1 ( 1h , d , j = 8 . 5 hz ), 5 . 45 ( 2h , m ), 5 . 05 ( 1h , t , j = 5 hz ), 4 . 65 ( 1h , d , j = 5 hz ), 4 . 1 ( 4h , m ), 2 . 4 ( 3h , s ). 13 c nmr ( cdcl 3 400 mhz ) δ 169 . 3 , 164 . 2 , 163 . 1 , 153 . 3 , 150 . 5 , 150 . 2 , 136 . 8 , 133 . 9 , 131 . 4 , 125 . 7 , 123 . 4 , 123 . 0 , 122 . 2 , 85 . 7 , 80 . 6 , 77 . 9 , 76 . 8 , 74 . 4 , 72 . 8 , 70 . 4 , 20 . 5 . hrms ( ei ) c 21 h 18 clno 8 , [ m + h ] + requires 448 . 8304 , found 448 . 8295 . anal . c 21 h 18 clno 8 requires c , 56 . 32 ; h , 4 . 05 ; n , 3 . 13 . found c , 56 . 20 ; h , 4 . 21 ; n , 3 . 02 . isosorbide - 2 - aspirinate 17 ( 250 mg , 0 . 8 mmol ) and 2 - chloro - 6 - methylpyridine - 4 - carbamoylchloride ( 247 mg , 0 . 9 mmol ) were reacted together according to gp2 to give 196 mg ( 53 %) of a white foam after flash chromatography with etoac : hex 2 : 6 . 1 h nmr ( cdcl 3 , 400 mhz ) δ 8 . 0 ( 1h , dd , j = 8 hz , 1 . 5 hz ), 7 . 74 ( 1h , s ), 7 . 68 ( 1h , s ) 7 . 6 ( 1h , dt , j = 8 hz , 1 . 5 hz ), 7 . 45 ( 1h , t , j = 1 hz ) 7 . 35 ( 1h , dt , j = 6 . 5 hz , 1 hz ), 7 . 1 ( 1h , d , j = 8 . 5 hz ), 5 . 45 ( 2h , m ), 5 . 05 ( 1h , t , j = 5 hz ), 4 . 65 ( 1h , d , j = 5 hz ), 4 . 1 ( 4h , m ), 2 . 65 ( 3h , s ), 2 . 4 ( 3h , s ). 13 c nmr ( cdcl 3 400 mhz ) δ 169 . 3 , 163 . 1 , 151 . 1 , 150 . 2 , 139 . 3 , 134 . 0 , 131 . 4 , 125 . 7 , 123 . 4 , 122 . 1 , 120 . 8 , 120 . 4 , 85 . 7 , 80 . 4 , 77 . 8 , 77 . 6 , 75 . 1 , 72 . 8 , 70 . 2 , 23 . 8 , 20 . 5 . hrms ( ei ) c 22 h 20 clno 8 , [ m + h ] + requires 462 . 8570 , found 462 . 8601 . anal . c 22 h 20 clno 8 requires c , 57 . 21 ; h , 4 . 36 ; n , 3 . 03 . found c , 56 . 91 ; h , 4 . 38 ; n , 2 . 94 . isosorbide - 2 - aspirinate 17 ( 200 mg , 0 . 65 mmol ) and 3 , 5 - ethoxybenzoyl chloride ( 157 mg , 0 . 72 mmol ) were reacted together according to gp2 to give 296 mg ( 74 %) of a viscous yellow oil after flash chromatography with etoac : hex 1 : 4 . 1 h nmr ( cdcl 3 , 400 mhz ) δ 8 . 1 ( 1h , d , j = 8 hz , asp h5 ), 7 . 6 ( 1h , dt , j = 8 hz , 1 . 5 hz , asp h4 ), 7 . 35 ( 1h , t , j = 1 hz , asp h3 ), 7 . 2 ( 2h , d , 1 hz , benz h2 + 6 ), 7 . 1 ( 1h , d , 8 . 5 hz , asp h2 ), 6 . 7 ( 1h , t , j = 2 . 25 hz , benz h4 ), 5 . 45 ( 2h , m , is h5 + h2 ), 5 . 05 ( 1h , t , j = 5 hz , is h4 ), 4 . 65 ( 1h , d , j = 5 . 5 hz , is h3 ), 4 . 05 ( 8h , m , is1 - h 2 [ α + β ], is6 - h 2 [ α + β ], ethoxy - ch 2 ), 2 . 4 ( 3h , s , acet - ch 3 ), 1 . 45 ( 6h , t , j = 3 . 5 hz , eto - ch 3 ). 13 c nmr ( cdcl 3 400 mhz ) δ 169 . 8 , 165 . 8 , 163 . 6 , 160 . 0 , 150 . 7 , 134 . 3 , 131 . 9 , 131 . 1 , 126 . 1 , 123 . 8 , 122 . 7 , 107 . 9 , 106 . 6 , 86 . 1 , 81 . 1 , 78 . 6 , 76 . 7 , 74 . 5 , 73 . 2 , 71 . 0 , 63 . 8 , 61 . 2 , 20 . 9 , 14 . 8 . hrms ( ei ) c 26 h 28 o 10 , [ m + h ] + requires 500 . 4945 , found 500 . 4932 . anal . c 26 h 28 o 10 requires c , 62 . 39 ; h , 5 . 64 . found c , 62 . 45 ; h , 5 . 79 . isosorbide - 2 - aspirinate 17 ( 200 mg , 0 . 65 mmol ) and 3 - methyl - isoxazole - 4 - carboxylic acid ( 127 mg , 0 . 72 mmol ) were reacted together according to gp1 to give 228 mg ( 83 %) of a white foam after flash chromatography with etoac : hex 1 : 3 . 1 h nmr ( cdcl 3 , 400 mhz ) δ 8 . 55 ( 1h , s , isox ), 8 . 0 ( 1h , d , j = 8 hz , asp h5 ), 7 . 65 ( 1h , dt , j = 8 hz , 1 . 5 hz , asp h4 ), 7 . 3 ( 1h , t , j = 1 hz , asp h3 ), 7 . 1 ( 1h , d , 8 . 5 hz , asp h2 ), 5 . 4 ( 2h , m , is h5 + h2 ), 5 . 0 ( 1h , t , j = 5 hz , is h4 ), 4 . 6 ( 1h , d , j = 5 . 5 hz , is h3 ), 4 . 1 ( 4h , m , is1 - h 2 [ α + β ], is6 - h 2 [ α + β ]), 3 . 8 ( 3h , s , isox - ch 3 ), 2 . 35 ( 3h , s , asp - acet - ch 3 ). 13 c nmr ( cdcl 3 400 mhz ) δ 169 . 2 , 163 . 0 , 160 . 4 , 150 . 2 , 149 . 6 , 133 . 9 , 131 . 4 , 125 . 6 , 123 . 4 , 122 . 1 , 85 . 6 , 80 . 5 , 73 . 9 , 72 . 7 , 70 . 2 , 33 . 5 , 24 . 5 , 20 . 5 , 12 . 3 . isosorbide - 2 - aspirinate 17 ( 200 mg , 0 . 65 mmol ) and 4 - methyl - 1 , 2 , 3 - thiadiazole - 5 - carboxylic acid were reacted together to give 228 mg ( 83 %) of a pale pink foam after flash chromatography with etoac : hex 1 : 3 . 1 h nmr ( cdcl 3 , 400 mhz ) δ 8 . 1 ( 1h , d , j = 8 hz , asp h5 ), 7 . 7 ( 1h , dt , j = 8 hz , 1 . 5 hz , asp h4 ), 7 . 35 ( 1h , t , j = 1 hz , asp h3 ), 7 . 15 ( 1h , d , 8 . 5 hz , asp h2 ), 5 . 5 ( 2h , m , is h5 + h2 ), 5 . 05 ( 1h , t , j = 5 hz , is h4 ), 4 . 65 ( 1h , d , j = 5 . 5 hz , is h3 ), 4 . 1 ( 4h , m , is1 - h 2 [ α + β ], is6 - h 2 [ α + β ]), 3 . 05 ( 3h , s , thiad - ch 3 ), 2 . 4 ( 3h , s , asp - acet - ch 3 ). 13 c nmr ( cdcl 3 400 mhz ) δ 169 . 7 , 163 . 5 , 162 . 9 , 159 . 1 , 150 . 7 , 134 . 4 , 131 . 8 , 126 . 1 , 123 . 8 , 122 . 5 , 86 . 2 , 80 . 9 , 78 . 2 , 75 . 9 , 73 . 2 , 70 . 8 , 21 . 0 , 14 . 1 . isosorbide - 2 - aspirinate 17 ( 200 mg , 0 . 65 mmol ) and 4n - boc - isonipecotic acid ( 162 mg , 0 . 72 mmol ) were reacted together to give 166 mg ( 49 %) of an off white oil after flash chromatography with meoh : dcm 3 : 97 . 1 h nmr ( cdcl 3 , 400 mhz ) δ8 . 1 ( 1h , d , j = 8 hz , asp h5 ), 7 . 7 ( 1h , dt , j = 8 hz , 1 . 5 hz , asp h4 ), 7 . 35 ( 1h , t , j = 1 hz , asp h3 ), 7 . 15 ( 1h , d , 8 . 5 hz , asp h2 ), 5 . 5 ( 1h , d , j = 1 . 5 hz is h2 ), 5 . 5 , ( 1h , dd , j = 5 hz , 1 hz ) 4 . 95 ( 1h , t , j = 5 hz , is h4 ), 4 . 65 ( 1h , d , j = 5 . 5 hz , is h3 ), 4 . 1 ( 8h , m , is1 - h 2 [ α + β ], is6 - h 2 [ α + β ], 4 nip h ), 2 . 6 ( 1h , m , nip - methine - h ), 2 . 4 ( 3h , s , asp - acet - ch 3 ), 1 . 7 ( 4h , m , 4 nip h ), 1 . 5 , ( 9h , s , t - bu ). 13 c nmr ( cdcl 3 400 mhz ) δ 173 . 9 , 169 . 8 , 163 . 5 , 154 . 7 , 150 . 7 , 134 . 4 , 131 . 9 , 126 . 1 , 123 . 9 , 122 . 6 , 85 . 9 , 80 . 7 , 79 . 6 , 78 . 5 , 77 . 2 , 76 . 5 , 73 . 9 , 73 . 0 , 70 . 7 , 42 . 9 , 40 . 9 , 28 . 4 , 28 . 1 , 27 . 9 , 20 . 9 . hrms ( ei ) c 26 h 33 o 10 n , [ m + h ] + requires 520 . 4616 , found 520 . 4631 . anal . c 26 h 33 o 10 n requires c , 60 . 11 ; h , 6 . 40 ; n , 2 . 69 . found c , 60 . 15 ; h , 6 . 79 ; n , 2 . 76 . isosorbide - 2 - aspirinate 17 ( 200 mg , 0 . 65 mmol ) and m - acetamidobenzoic acid ( 128 mg , 0 . 72 mmol ) were reacted together to give 202 mg ( 66 %) of a white solid after flash chromatography with meoh : dcm 3 : 97 . 1 h nmr ( cdcl 3 , 400 mhz ) δ8 . 0 ( 3h , m , asp h5 , ar h2 + 4 ), 7 . 85 ( 1h , d , j = 8 hz , ar h6 ), 7 . 6 ( 1h , dt , j = 8 hz , 1 . 5 hz , asp h4 ), 7 . 45 ( 1h , t , j = 7 . 5 hz , ar h5 ), 7 . 35 ( 1h , t , j = 1 hz , asp h3 ), 7 . 15 ( 1h , d , 8 . 5 hz , asp h2 ), 5 . 5 ( 2h , m , is h5 + h2 ), 5 . 05 ( 1h , t , j = 5 hz , is h4 ), 4 . 65 ( 1h , d , j = 5 . 5 hz , is h3 ), 4 . 1 ( 4h , m , is1 - h 2 [ α + β ], is6 - h 2 [ α + β ]), 2 . 4 ( 3h , s , asp - acet - ch 3 ), 2 . 2 ( 3h , ar - acet - ch 3 ). 13 c nmr ( cdcl 3 400 mhz ) δ 169 . 3 , 168 . 0 , 165 . 0 , 163 . 1 , 150 . 2 , 137 . 7 , 133 . 9 , 131 . 4 , 129 . 7 , 128 . 9 , 125 . 6 , 125 . 0 , 124 . 4 , 123 . 4 , 122 . 2 , 120 . 2 , 85 . 7 , m80 . 7 , 78 . 1 , 74 . 12 , 72 . 8 , 70 . 4 , 60 . 0 , 24 . 2 , 20 . 5 , 13 . 8 . hrms ( ei ) c 24 h 23 o 9 n , [ m + h ] + requires 470 . 4392 , found 470 . 4403 . anal . c 24 h 23 o 9 n requires c , 61 . 41 ; h , 4 . 93 ; n , 2 . 98 . found c , 61 . 52 ; h , 5 . 09 ; n , 2 . 86 . isosorbide - 2 - aspirinate 17 ( 250 mg , 0 . 8 mmol ) and m - benzyloxybenzoic acid ( 182 mg , 0 . 88 mmol ) were reacted together according to gp1 to give 346 mg ( 85 %) of a white solid after flash chromatography with etoac : hex 1 : 2 . 1 h nmr ( cdcl 3 , 400 mhz ) δ 8 . 0 ( 1h , d , j = 8 hz , asp h5 ), 7 . 7 ( 3h , m , asp h4 , ar2h ), 7 . 35 ( 2h , m , asp h3 , arh ), 7 . 1 ( 2h , m , asp h2 , arh ), 7 . 25 ( 5h , m , bnh ), 5 . 5 ( 3h , m , is h2 , bn - ch 2 ), 5 . 05 ( 1h , t , j = 5 hz , is h4 ), 4 . 65 ( 1h , d , j = 5 . 5 hz , is h3 ), 4 . 1 ( 4h , m , is1 - h 2 [ α + β ], is6 - h 2 [ α + β ]), 2 . 4 ( 3h , s , asp - acet - ch 3 ). 13 c nmr ( cdcl 3 400 mhz ) δ 169 . 76 , 165 . 2 , 163 . 6 , 150 . 7 , 135 . 8 , 134 . 4 , 133 . 7 , 132 . 9 , 131 . 9 , 130 . 8 , 130 . 3 , 130 . 2 , 129 . 2 , 126 . 1 , 123 . 9 , 122 . 7 , 97 . 7 , 86 . 1 , 81 . 1 , 78 . 5 , 74 . 7 , 73 . 2 , 70 . 8 , 43 . 9 , 20 . 9 . hrms ( ei ) c 29 h 26 o 9 , [ m + h ] + requires 518 . 4344 , found 518 . 4357 . anal . c 29 h 26 o 9 requires c , 67 . 19 ; h , 5 . 05 . found c , 67 . 28 ; h , 5 . 09 . isosorbide - 2 - aspirinate ( 250 mg , 0 . 8 mmol ) and m - benzyloxybenzoic acid ( 182 mg , 0 . 88 mmol ) were reacted together according to gp1 to give 346 mg ( 85 %) of a white solid after flash chromatography with etoac : hex 1 : 2 . 1 h nmr ( cdcl 3 , 400 mhz ) δ 8 . 0 ( 1h , d , j = 8 hz , asp h5 ), 7 . 7 ( 1h , dt , j = 8 hz , 1 . 5 hz , asp h4 ), 7 . 45 ( m , 4h , arh ), 7 . 35 ( 1h , t , j = 1 hz , asp h3 ), 7 . 25 ( 5h , m , bnh ) 7 . 1 ( 1h , d , 8 . 5 hz , asp h2 ), 5 . 5 ( 3h , m , is h2 , bn - ch 2 ), 5 . 05 ( 1h , t , j = 5 hz , is h4 ), 4 . 65 ( 1h , d , j = 5 . 5 hz , is h3 ), 4 . 1 ( 4h , m , is1 - h 2 [ α + β ], is6 - h 2 [ α + β ]), 2 . 4 ( 3h , s , asp - acet - ch 3 ). 13 c nmr ( cdcl 3 400 mhz ) δ 169 . 76 , 165 . 2 , 163 . 6 , 150 . 7 , 136 . 9 , 135 . 2 , 133 . 0 , 132 . 2 , 131 . 9 , 130 . 8 , 130 . 3 , 130 . 2 , 129 . 2 , 126 . 1 , 123 . 9 , 122 . 7 , 97 . 7 , 86 . 1 , 81 . 1 , 78 . 5 , 74 . 7 , 73 . 2 , 70 . 8 , 43 . 9 , 20 . 9 . hrms ( ei ) c 29 h 26 o 9 , [ m + h ] + requires 518 . 4344 , found 518 . 4338 . anal . c 29 h 26 o 9 requires c , 67 . 19 ; h , 5 . 05 . found c , 67 . 35 ; h , 5 . 18 . phthalide ( m . w . 134 . 13 g / mol , 5 . 03 g = 37 mmol ) and dichlorotriphenylphosphorane ( m . w . 333 . 19 g / mol , 12 . 3 g = 38 mmol ) were heated at 180 ° c . for 4 hrs with stirring [ 3 ] . colour change from green to brown was seen over the course of 4 hrs . tlc ( hexane / ethyl acetate 2 : 1 ) showed 3 spots and nmr determined that the top spot ( rf 0 . 77 ) was that of 2 - chloromethylbenzoyl chloride , the second spot ( rf 0 . 57 ) was phthalide and the bottom spot ( rf 0 . 14 ) was triphenylphosphorous . a large amount of the phthalide was unreacted . 2 - chloromethylbenzoyl chloride ( fig1 ) ( m . w . 189 . 04 g / mol , 600 μl ) was dissolved in dichloromethane ( 10 ml ). triethylamine ( m . w . 101 . 19 g / mol , d = 0 . 726 g / ml , 600 μl = 4 . 3 mmol ) was added and the mixture was cooled to 0 ° c . compound 17 ( m . w . 308 . 14 g / mol , 0 . 5298 g = 1 . 7 mmol ) was added and the mixture was stirred at room temperature overnight while protected from light . the mixture ( green colour ) was washed with hcl ( 2 m , 10 ml ), 5 % nahco 3 ( 10 ml ) and distilled water ( 10 ml ) and dried over sodium sulfate . mixture was concentrated producing 769 . 5 mg of a brown / green oil . this was chromatographed using hexane / ethyl acetate ( 2 : 1 ) resulting in 419 . 4 mg of a brown solid ( rf 0 . 38 ). 1 h nmr δ ( cdcl 3 ) 400 mhz : 2 . 38 ( 3h , s , ococ h 3 ), 4 . 03 ( 4h , m , ish - 1 , ish - 1 ′, ish - 6 and ish - 6 ′), 4 . 66 ( 1h , d , ish - 3 ), 5 . 04 ( 2h , m , c h 2 cl ), 5 . 10 ( 1h , ss , ish - 4 ), 5 . 42 ( 2h , m , ish - 2 / h - 5 ), 7 . 12 ( 1h , d , ar — h ), 7 . 28 ( 1h , m , ar — h ), 7 . 42 ( 1h , m , ar — h ), 7 . 6 ( 3h , m , ar — h ), 8 . 01 ( 2h , dd , ar — h ). 13 c nmr ppm ( cdcl 3 ) 400 mhz : 20 . 51 ( oco c h 3 ), 43 . 95 ( c h 2 cl ), 70 . 15 ( isc - 1 ), 72 . 78 ( isc - 6 ), 74 . 33 ( isc - 5 ), 78 . 11 ( isc - 2 ), 80 . 52 ( isc - 4 ), 85 . 58 ( isc - 3 ), 122 . 21 ( ar 2 c - 2 / c - 6 ), 123 . 42 , 125 . 65 ( ar 2 c - 4 ), 128 . 03 ( ar 1 c - 6 ), 128 . 07 ( ar 1 c - 2 ), 130 . 60 ( ar 1 c - 5 ), 130 . 73 ( ar1c - 1 ), 131 . 43 ( ar 1 c - 4 ), 133 . 45 ( ar 2 c - 5 ), 133 . 92 , 138 . 54 , 150 . 25 ( ar 2 o c o ), 163 . 12 ( o c oarch 2 ono 2 ), 165 . 47 ( aro c och 3 ), 169 . 29 ( ar c ( o ) or ). 400 mg was dissolved in ch 3 cn / thf ( 6 ml , 4 / 2 v / v ) and treated with agno 3 ( m . w . 169 . 87 g / mol , 0 . 30 g = 1 . 7 mmol ) and refluxed for 4 hours before stirring overnight at room temperature while protected from light . mixture was filtered and concentrated . this was reconstituted in ethyl acetate ( 10 ml ) and water ( 2 ml ). the organic phase was washed with water ( 3 × 2 ml ), brine ( 2 ml ) and dried over sodium sulfate . concentrated , producing an oil which was chromatographed using hexane / ethyl acetate ( 2 : 1 ) resulting in 95 mg of yellow wax - like material . 1 h nmr δ ( cdcl 3 ) 400 mhz : 2 . 38 ( 3h , s , ococ h 3 ), 4 . 01 ( 4h , m , ish - 1 , ish - 1 ′, ish - 6 and ish - 6 ′), 4 . 65 ( 1h , d , ish - 3 ), 5 . 02 ( 1h , t , ish - 4 ), 5 . 41 ( 2h , m , c h 2 ), 5 . 86 ( 2h , ss , ish - 2 / h - 5 ), 7 . 11 ( 1h , d , ar — h ), 7 . 28 ( 1h , t , ar — h ), 7 . 49 ( 2h , q , ar — h ), 7 . 61 ( 2h , q , ar — h ), 8 . 01 ( 1h , d , ar — h ), 8 . 10 ( 1h , d , ar — h ). 13 c nmr ppm ( cdcl 3 ) 400 mhz : 20 . 51 ( oco c h 3 ), 70 . 37 ( c h 2 ono 2 ), 72 . 78 ( isc - 1 ), 73 . 46 ( isc - 6 ), 74 . 30 ( isc - 5 ), 78 . 01 ( isc - 2 ), 80 . 61 ( isc - 4 ), 85 . 64 ( isc - 3 ), 122 . 19 ( ar 2 c - 2 / c - 6 ), 123 . 40 , 125 . 66 ( ar 2 c - 4 ), 128 . 76 ( ar 1 c - 6 ), 129 . 77 ( ar 1 c - 2 ), 129 . 85 ( ar 1 c - 5 ), 130 . 30 ( ar1c - 1 ), 131 . 41 ( ar 1 c - 4 ), 132 . 44 ( ar 2 c - 5 ), 133 . 25 , 133 . 93 , 150 . 23 ( ar 2 o c o ), 163 . 12 ( o c oarch 2 ono 2 ), 164 . 71 ( aro c och 3 ), 169 . 28 ( ar c ( o ) or ). 3 - chloromethylbenzoyl chloride ( m . w . 189 . 04 g / mol , d = 1 . 33 g / ml , 500 μl = 3 . 5 mmol ) was dissolved in dichloromethane ( 10 ml ). triethylamine ( m . w . 101 . 19 g / mol , d = 0 . 726 g / ml , 600 μl = 4 . 3 mmol ) was added and the mixture was cooled to 0 ° c . compound 17 ( m . w . 308 . 14 g / mol , 0 . 511 g = 1 . 6 mmol ) was added and the mixture was stirred at room temperature overnight while protected from light . the mixture was washed with hcl ( 2 m , 10 ml ), 5 % nahco 3 ( 10 ml ) and distilled water ( 10 ml ) and dried over sodium sulfate . mixture was concentrated producing 1 . 18 g of an oil . this was chromatographed using hexane / ethyl acetate ( 3 : 1 ) resulting in 903 . 4 mg of an oil ( rf 0 . 2 ). 1 h nmr δ ( cdcl 3 ) 400 mhz : 2 . 37 ( 3h , s , ococ h 3 ), 4 . 06 ( 4h , m , ish - 1 , ish - 1 ′, ish - 6 and ish - 6 ′), 4 . 65 ( 3h , ds , ish - 3 and ch 2 cl ), 5 . 03 ( 1h , t , ish - 4 ), 5 . 43 ( 2h , dd , ish - 2 , ish - 5 ), 7 . 10 ( 1h , d , ar — h ), 7 . 32 ( 1h , t , ar — h ), 7 . 47 ( 1h , t , ar — h ), 7 . 57 ( 2h , m , ar — h ), 8 . 00 ( 2h , m , ar — h ), 8 . 10 ( 1h , s , ar — h ). 13 c nmr ppm ( cdcl 3 ) 400 mhz : 20 . 49 ( oco c h 3 ), 45 . 01 ( c h 2 cl ), 70 . 41 ( isc - 1 ), 72 . 76 ( isc - 6 ), 74 . 20 ( isc - 5 ), 78 . 04 ( isc - 2 ), 80 . 64 ( isc - 4 ), 85 . 63 ( isc - 3 ), 122 . 18 ( ar 2 c - 2 / c - 6 ), 123 . 39 , 125 . 67 ( ar 2 c - 4 ), 128 . 61 ( ar 1 c - 6 ), 129 . 28 ( ar 1 c - 2 ), 129 . 36 ( ar 1 c - 5 ), 129 . 52 ( ar1c - 1 ), 131 . 41 ( ar 1 c - 4 ), 133 . 02 ( ar 2 c - 5 ), 133 . 93 , 137 . 57 , 150 . 20 ( ar 2 o c o ), 163 . 16 ( o c oarch 2 ono 2 ), 164 . 94 ( aro c och 3 ), 169 . 37 ( ar c ( o ) or ). this was dissolved in ch 3 cn / thf ( 6 ml , 4 / 2 v / v ) and treated with agno 3 ( m . w . 169 . 87 g / mol , 0 . 67 g = 3 . 9 mmol ) and refluxed for 4 hours before stirring overnight at room temperature while protected from light . mixture was filtered and concentrated . this was reconstituted in ethyl acetate ( 10 ml ) and water ( 2 ml ). the organic phase was washed with water ( 3 × 2 ml ), brine ( 2 ml ) and dried over sodium sulfate . concentrated , producing an oil which was chromatographed using hexane / ethyl acetate ( 1 : 1 ) resulting in 184 . 3 mg of yellow wax - like material . 1 h nmr δ ( cdcl 3 ) 400 mhz : 2 . 38 ( 3h , s , ococ h 3 ), 4 . 09 ( 4h , m , ish - 1 , ish - 1 ′, ish - 6 and ish - 6 ′), 4 . 65 ( 1h , d , ish - 3 ), 5 . 05 ( 1h , t , ish - 4 ), 5 . 5 ( 4h , dd , ish - 2 , ish - 5 and c h 2 ), 7 . 12 ( 1h , d , ar — h ), 7 . 29 ( 1h , t , ar — h ), 7 . 50 ( 3h , m , ar — h ), 7 . 65 ( 1h , d , ar — h ), 8 . 01 ( 2h , broad s , ar — h ). 13 c nmr ppm ( cdcl 3 ) 400 mhz : 20 . 51 ( oco c h 3 ), 70 . 37 ( c h 2 ono 2 ), 72 . 78 ( isc - 1 ), 73 . 46 ( isc - 6 ), 74 . 30 ( isc - 5 ), 78 . 01 ( isc - 2 ), 80 . 61 ( isc - 4 ), 85 . 64 ( isc - 3 ), 122 . 19 ( ar 2 c - 2 / c - 6 ), 123 . 40 , 125 . 66 ( ar 2 c - 4 ), 128 . 76 ( ar 1 c - 6 ), 129 . 77 ( ar 1 c - 2 ), 129 . 85 ( ar 1 c - 5 ), 130 . 30 ( ar1c - 1 ), 131 . 41 ( ar 1 c - 4 ), 132 . 44 ( ar 2 c - 5 ), 133 . 25 , 133 . 93 , 150 . 23 ( ar 2 o c o ), 163 . 12 ( o c oarch 2 ono 2 ), 164 . 71 ( aro c och 3 ), 169 . 28 ( ar c ( o ) or ). 4 - chloromethylbenzoyl chloride ( m . w . 189 . 04 g / mol , 650 μl ) was dissolved in dichloromethane ( 10 ml ). triethylamine ( m . w . 101 . 19 g / mol , d = 0 . 726 g / ml , 600 μl = 4 . 3 mmol ) was added and the mixture was cooled to 0 ° c . compound 17 ( m . w . 308 . 14 g / mol , 0 . 5320 g = 1 . 7 mmol ) was added and the mixture was stirred at room temperature overnight while protected from light . the mixture was washed with hcl ( 2 m , 10 ml ), 5 % nahco 3 ( 10 ml ) and distilled water ( 10 ml ) and dried over sodium sulfate . mixture was concentrated and was chromatographed using hexane / ethyl acetate ( 2 : 1 ) resulting in 100 mg of white solid material . 1 h nmr δ ( cdcl 3 ) 400 mhz : 2 . 35 ( 3h , s , ococ h 3 ), 4 . 04 ( 4h , m , ish - 1 , ish - 1 ′, ish - 6 and ish - 6 ′), 4 . 6 ( 4h , m , ish - 3 and c h 2 cl , imp ), 5 . 04 ( 1h , d , ish - 4 ), 5 . 42 ( 2h , t , ish - 2 , ish - 5 ), 7 . 09 ( 1h , d , ar — h ), 7 . 26 ( 1h , t , ar — h ), 7 . 47 ( 2h , m , ar — h ), 7 . 51 ( 1h , q , ar — h ), 8 . 00 ( 1h , d , ar — h ), 8 . 06 ( 2h , m , ar — h ). 13 c nmr ppm ( cdcl 3 ) 400 mhz : 20 . 51 ( oco c h 3 ), 44 . 87 ( c h 2 cl ), 70 . 47 ( isc - 1 ), 72 . 76 ( isc - 6 ), 74 . 11 ( isc - 5 ), 78 . 05 ( isc - 2 ), 80 . 67 ( isc - 4 ), 85 . 64 ( isc - 3 ), 122 . 22 ( ar 2 c - 2 / c - 6 ), 123 . 40 , 125 . 65 ( ar 2 c - 4 ), 128 . 53 ( ar 1 c - 6 ), 128 . 96 ( ar 1 c - 2 ), 129 . 77 ( ar 1 c - 5 ), 130 . 16 ( ar1c - 1 ), 130 . 56 ( ar 1 c - 4 ), 131 . 43 ( ar 2 c - 5 ), 139 . 91 , 142 . 23 , 150 . 23 ( ar 2 o c o ), 163 . 14 ( o c oarch 2 ono 2 ), 164 . 91 ( aro c och 3 ), 169 . 31 ( ar c ( o ) or ). this was dissolved in ch 3 cn / thf ( 6 ml , 4 / 2 v / v ) and treated with agno 3 ( m . w . 169 . 87 g / mol , 75 mg = 0 . 4 mmol ) and refluxed for 4 hours before stirring overnight at room temperature while protected from light . mixture was filtered and concentrated . this was reconstituted in ethyl acetate ( 10 ml ) and water ( 2 ml ). the organic phase was washed with water ( 3 × 2 ml ), brine ( 2 ml ) and dried over sodium sulfate . concentrated , producing an oil which was chromatographed using hexane / ethyl acetate ( 2 : 1 ) resulting in 28 . 3 mg of off - white solid . 1 h nmr δ ( cdcl 3 ) 400 mhz : 2 . 35 ( 3h , s , ococ h 3 ), 4 . 04 ( 4h , m , ish - 1 , ish - 1 ′, ish - 6 and ish - 6 ′), 4 . 62 ( 1h , d , ish - 3 ), 5 . 01 ( 1h , t , ish - 4 ), 5 . 41 ( 2h , m , c h 2 ), 5 . 48 ( 2h , s , ish - 2 / h - 5 ), 7 . 09 ( 1h , d , ar — h ), 7 . 31 ( 1h , t , ar — h ), 7 . 48 ( 2h , d , ar — h ), 7 . 55 ( 1h , t , ar — h ), 8 . 00 ( 1h , d , ar — h ), 8 . 10 ( 2h , d , ar — h ). 13 c nmr ppm ( cdcl 3 ) 400 mhz : 20 . 51 ( ococh 3 ), 70 . 44 ( c h 2 ono 2 ), 72 . 76 ( isc - 1 ), 73 . 18 ( isc - 6 ), 74 . 23 ( isc - 5 ), 78 . 02 ( isc - 2 ), 80 . 65 ( isc - 4 ), 85 . 65 ( isc - 3 ), 122 . 19 ( ar 2 c - 2 / c - 6 ), 123 . 41 , 125 . 66 ( ar 2 c - 4 ), 128 . 17 ( ar 1 c - 6 ), 129 . 85 ( ar 1 c - 2 ), 129 . 92 ( ar 1 c - 5 ), 131 . 41 ( ar1c - 1 ), 133 . 93 ( ar 1 c - 4 ), 137 . 19 ( ar 2 c - 5 ), 150 . 24 ( ar 2 o c o ), 163 . 14 ( o c oarch 2 ono 2 ), 164 . 75 ( aro c och 3 ), 169 . 29 ( ar c ( o ) or ). to a solution of isosorbide - 2 - aspirinate 17 ( 0 . 49 g , 1 . 6 mmol ) in dichloromethane ( 10 ml ) was added dcc ( 0 . 33 g , 1 . 6 mmol ), dmap ( 0 . 02 g , 0 . 16 mmol ) and nitrooxy acetic acid ( 0 . 19 g , 1 . 6 mmol ). the mixture was stirred at room temperature overnight before filtering and washing the filtrate with hcl ( 2 × 10 ml , 0 . 1 m ), saturated aqueous nahco 3 ( 2 × 10 ml ) and water ( 2 × 10 ml ). after drying over anhydrous na 2 so 4 , the dichloromethane was removed in vacuo to afford product as crude oil . purification by column chromatography over silica gel using hexane and ethyl acetate ( 5 : 2 ) as eluant yielded compound 23 ( 0 . 38 g ) as colorless oil . ir vmax ( film ) cm − 1 : 1759 . 0 and 1727 . 5 ( c ═ o ), 1643 . 6 ( no 2 ), 1287 . 7 ( no 2 ), 1256 . 3 ( c ( o ) or , aromatic ), 1193 . 5 ( c — o — c ). hrms : requires 411 . 0802 ( m + ), found : ( m + ). δh ( 400 mhz ; cdcl 3 ): 2 . 36 ( 3h , s , ococh 3 ), 2 . 68 ( 1h , d , j 7 . 52 hz , is — h ), 3 . 61 ( 1h , q , j 6 . 04 , 3 . 52 and 6 hz , is — h ), 3 . 92 ( 1h , q , j 6 . 04 , 3 . 52 and 6 hz , is — h ), 4 . 12 ( 2h , m , is — h 2 ), 4 . 33 ( 1h , m , is — h 2 ). 4 . 58 ( 1h , d , j 4 hz , is — h ), 4 . 67 ( 1h , t , j 5 and 5 . 04 hz , is — h ), 5 . 44 ( 2h , s , och 2 o ), 7 . 11 ( 1h , d , j 8 . 04 hz , ar — h ), 7 . 33 ( 1h , t , j 8 and 7 . 52 hz , ar — h ), 7 . 59 ( 1h , t , 7 . 06 and 8 . 26 hz , ar — h ), 8 . 01 ( 1h , d , j 6 . 52 hz , ar — h ). δ 13 c ( 100 mhz ; cdcl 3 ): 20 . 91 ( ococh 3 ), ( ch 2 ), 72 . 36 ( is — c ), 73 . 41 ( is — c ), 73 . 69 ( is — c ), 78 . 96 ( is — c ), 82 . 04 ( is — c ), 85 . 64 ( is — c ), 122 . 77 ( arc - 1 ), 123 . 89 , 126 . 07 , 131 . 81 and 134 . 31 ( aromatic methine ), 150 . 74 ( co ), 163 . 51 ( aro c ( o ) me ), 169 . 59 ( ar c ( o ) or ). to a solution of is - 5 - mn ( 5 g , 26 . 65 mmol ) in toluene ( 100 ml ) at 0 ° c . was added triethylamine ( 5 . 52 ml , 3 . 96 mmol ) and acetylsalicyloyl chloride ( 6 . 31 g , 31 . 74 mmol ). the reaction was returned to room temperature and allowed to stir for 6 hours before washing with water ( 2 × 50 ml ), hcl ( 1 m , 2 × 50 ml ), saturated aqueous nahco 3 ( 2 × 50 ml ) and brine ( 100 ml ). the organic phase was dried with na 2 so 4 and solvent removed in vacuo to yield product as oil . this was crystallised from ethanol to yield 5 . 42 g of product as white crystals . ( 58 . 05 %): m . pt . 82 - 84 ° c . ir vmax ( kbr ): 1757 . 6 and 1733 . 4 ( c ═ o ), 1651 . 8 ( no 2 ), 1261 . 4 ( c ( o ) or , aromatic ), 915 . 5 ( ono 2 ) cm − 1 . hrms : requires : 376 . 0645 ( m + + 23 ), found : 376 . 0640 ( m + + 23 ). 1 h nmr δ ( cdcl 3 ): 2 . 37 ( 3h , s , ococh 3 ), 3 . 93 ( 1h , dd , j 6 . 0 , 11 . 5 and 6 . 0 hz , is6a - h ), 4 . 09 ( 3h , m , is1h [ αβ ] and is6h [ β ]), 4 . 58 ( 1h , d , j 4 . 5 hz , is3 - h ), 5 . 03 ( 1h , t , j 5 . 0 and 5 . 5 hz , is4 - h ), 5 . 38 ( 1h , m , is5 - h ), 5 . 45 ( 1h , d , j 3 . 0 hz , is2 - h ), 7 . 12 ( 1h , d , j 8 . 0 hz , ar — h ), 7 . 33 ( 1h , t , j 7 . 5 and 8 . 0 hz , ar — h ), 7 . 60 , ( 1h , t , j 7 . 5 and 8 . 0 hz , ar — h ), 8 . 01 ( 1h , d , j 7 . 5 hz , ar — h ). 13 c nmr ppm ( cdcl 3 ): 20 . 40 ( ococh 3 ), 68 . 88 and 72 . 84 ( isc - 1 and isc - 6 ), 77 . 50 ( isc - 5 ), 80 . 83 ( isc - 4 ), 81 . 08 ( isc - 2 ), 122 . 19 ( arc - 1 ), 123 . 41 , 125 . 61 , 131 . 37 , 133 . 92 ( aromatic methine ), 150 . 24 ( arc - 2 ), 163 . 09 ( aro c o ( me )), 169 . 17 ( arc ( o ) or ). pooled plasma / serum solutions ( 4 ml ) were prepared to the correct strength by dilution of plasma with phosphate buffer ph 7 . 4 ( e . g . for a 10 % solution 0 . 4 ml of plasma / serum was added to 3 . 6 ml of phosphate buffer ph 7 . 4 ). following equilibration of the plasma / serum sample at 37 ± 0 . 5 ° c . 100 μl of a stock solution of test compound in acetonitrile ( 1 × 10 − 4 m ) was added and 250 μl aliquots were removed at specified time intervals . samples were transferred to 1 . 5 ml eppendorf tubes containing 500 μl of a 2 % w / v solution of nso 4 . 7h 2 o ( water : acetonitrile , 1 : 1 ). tubes were vortexed for 2 minutes , then centrifuged at 10 , 000 rpm for 3 minutes at room temperature . supernatant was aspirated off and analysed by hplc . the concentration of test compound and metabolites were determined with reference to calibration curves run on that day in the same concentration range and under the same experimental conditions . in order to mimic conditions during the first passage of the drugs after intestinal absorption selected compounds were incubated in phosphate buffer at 37 ° c . in the presence of microsomes from human liver ( hlm ) and intestinal epithelium ( him ). the metabolic fate of the esters under these conditions was also determined by rphplc by measuring the concentration of drug and metabolites in the medium as a function of time . the identity of participating enzymes was confirmed by using purified enzyme in the case of plasma ( buche ) and by repeating the hydrolysis experiments in the presence of esterase specific inhibitors — isoompa for buche and bnpp for carboxylesterase . the buche activity of plasma and microsomal samples was determined using the ellman assay ( ellman et al ., 1964 ). high performance liquid chromatography was performed using a system consisting of a waters 600 pump and controller , waters 717 autosampler and a waters 2996 photodiode array detector controlled by empower software . a hichrom nucleosil c18 column ( 4 . 0 × 250 mm ) was used . mobile phase was filtered prior to use and sparged with helium throughout assays . the final gradient method used was as follows : the method was validated for linearity , precision and for the metabolites for loq and lod . developing a method that gave good separation of aspirin and salicylic acid was a lengthy task as the initial choice of a spherisorb ods c18 column with buffer ph 3 . 19 gave extreme tailing and poor separation ( buffer with a ph of 3 . 19 was chosen as it &# 39 ; s close to their pka &# 39 ; s — aspirin is 3 . 5 and salicylic acid is 2 . 97 [ 2 ] ). this was eventually solved by using the hichrom nucleosil column and buffer ph 2 . 5 . as aspirin is a weak acid with a pka of 3 . 5 reducing the buffer ph below its pka decreases retention as the compound becomes more hydrophobic . the nucleosil column gave excellent peak shape and resolution of the two compounds . initially monohydrate salts were used which produced a large buffer peak at 18 mins . using dihydrate salts eliminated the peak . although nearing the end of this work some large buffer peaks began to appear again . there are also methods for measuring platelet aggregation inhibition , txb 2 , platelet gp2b3a expression , mda and corresponding data that demonstrate that the key compounds have aspirin - like activity . a 500 μl aliquot of blood was mixed with 500 μl of physiological saline and allowed to incubate at 37 ° c . for 10 mins in the incubation well of a chrono - log whole blood aggregometer model 591 / 592 . the sample was then transferred to the assay well , baseline was established and appropriate volume of reagent as above was added . aggregation was monitored over 6 mins with impedance output recorded on a chart recorder . when testing inhibitors whole blood was pre - incubated with appropriate concentrations of inhibitor in dmso at 37 ° c . for a specified length of time before adding the stimulant ( 10 mins with stirring ). three different aggregating agents , aa ( 0 . 5 mm ), adp ( 10 μm ) and collagen ( 5 μg / ml ) were used . where no aggregation response was observed in the presence of an inhibitor a control experiment was performed with no inhibitor present . dmso in high concentrations ( above 0 . 25 %) can induce a concentration dependent change in platelet cytoplasmic ionised calcium . before each experiment a control was run using prp to obtain normal aggregating responses . a sample was also incubated for 10 min at 37 ° c . with 10 μl dmso to ensure it was having no inhibitory effect on the aggregation response . two metabolites of isas , salicylic acid and isosorbide were examined to determine if they had inhibitory effect on platelets . in this model isas exhibited significantly greater potency than aspirin or isda in the inhibition of platelet aggregation to all of the aggregatory stimuli . blood was collected from healthy volunteers who had not taken any drugs known to affect platelet function for at least 14 days prior to the study . platelet rich plasma ( prp ) and washed platelet suspensions ( 2 . 5 × 10 8 platelets / ml ) were prepared from blood as previously described . platelet aggregation was measured by light aggregometry as previously described . briefly , prp and washed platelet samples ( 2 . 5 × 10 8 / ml ) were placed in a whole blood ionized calcium lumi - aggregometer ( chronolog corp ., havertown , pa ., u . s . a ), and ( bio / data corporation ) and incubated for 10 min at 37 ° c ., with stirring at 900 r . p . m ., prior to the addition of aggregating agents . aggregation was initiated by the addition of agonists , and monitored by aggro - link software for at least 6 min . for experiments using inhibitors , aggregation was initiated after 10 min preincubation with these compounds to study the aggregatory potency of adp , the concentration - response ( 0 . 3 - 10 um ) curves were generated . collagen at different concentrations ( 3 - 5 ug / ml ) was also used to induce platelet aggregation . the submaximal concentrations of agonists , i . e . the concentrations that gave approximately 95 % of the maximal aggregation were used to study the effects of inhibitors of aggregation . results were expressed in percent changes in maximal light transmission , with 100 % representing light transmission of platelet medium alone . aspirin inhibits platelet aggregation by attenuating cyclooxygenase mediated synthesis of pgh2 , which is converted in cells to the powerful aggregator txa 2 by thromboxane synthase . txa 2 is highly evanescent and unsuitable for direct measurement but its metabolite txb 2 is generally believed to provide a useful index of the parent . aspirin treatment of tissue in vivo or in vitro is reflected in a depression of txb 2 . in order to compare the compounds of the invention with aspirin in this regard untreated whole blood was allowed to clot in the presence of aspirin or the test compounds over the course of 1 hour at 37 ° c . the samples were then centrifuged . serum was collected and txb 2 was measured using enzyme linked immunosorbent assay ( elisa ) kits obtained from cayman chemicals . the experiments were performed with aspirin in descending concentration from values that gave complete inhibition of txb 2 synthesis . in these assays isas was significantly more potent than aspirin as reflected in a lower ic 50 . in order to analyze receptor expression on the surface of individual platelets and to minimize platelet activation caused by sample preparation procedures , no stirring or vortexing steps were used . the abundance of activated gpiib / iiia and p - selectin on the surface of platelets in the presence and absence of inhibitors was measured by flow cytometry . platelet samples were first activated with agonists either collagen or adp . when platelet aggregation reached 50 % maximal light transmission the reaction was terminated by 10 - fold dilution with physiologic saline . resting platelets were used as control . in most of the experiments , platelets were preincubated with inhibitors for 10 min prior to the addition of agonists . platelet samples were then incubated in the dark without stirring for 5 min at room temperature in the presence of saturating concentrations ( 10 μg / ml ) of p - selectin ( cd62p - apc ). the activated gpiib / iiia platelet receptors were measured using pac - 1 monoclonal antibody at the same concentration as above . pac - 1 specifically recognizes an epitope on the high - affinity gpiib / iiia complex of activated platelets at or near the platelet 5 . following incubation , samples were diluted in facs flow fluid and analyzed within 5 min using a bd facsarray ( bd biosciences , oxford , uk ). flow cytometry was performed on single stained platelet samples as described before 3 . the instrument was set up to measure the size ( forward scatter ), granularity ( side scatter ) and cell fluorescence . a two - dimensional analysis gate of forward and side scatter was drawn in order to include single platelets and exclude platelet aggregates and microparticles . antibody binding was measured by analyzing individual platelets for fluorescence . the mean fluorescence intensity was determined after correction for cell autofluorescence . for each sample , the fluorescence was analyzed using a logarithmic scale . fluorescence histograms were obtained for 10 , 000 individual events . data were analyzed using cytometer rxp software and expressed as a percentage of control fluorescence in arbitrary units . human blood samples were collected by venipuncture into li - heparin sarstedt monovette tubes ( 9 ml ). plasma samples were obtained by centrifugation of blood at 10 , 000 rpm for five minutes and were frozen in aliquots until required for testing . pooled human liver microsomes ( hlm ) were diluted to 5 ml with phosphate buffer ph 7 . 4 ( 0 . 1m ) giving a stock solution of 2 mg / ml . aliquots were frozen until required for testing . pooled human intestinal microsomes ( him ) were diluted to 5 ml with phosphate buffer ph 7 . 4 ( 0 . 1m ) giving a stock solution of 80 μg / ml . aliquots were frozen until required for testing . butyrylcholinesterase ( bche ) activity in hlm and him was determined spectrophotometrically ( 405 nm ) at 37 ° c . by the ellman method ( ellman et al ., 1964 ). butyrylthiocholine iodide ( btci ) ( 0 . 5 mm ) was used as the substrate . the reaction took place in a 96 - well plate with a final volume of 250 μl . initially phosphate buffer ph 8 . 0 ( 0 . 1m ) and microsomes were mixed and incubated for 30 mins . dtnb ( 0 . 3 mm ) and btci were added and the reaction was measured . the assay was also performed using sonication bursts ( 4 × 5 sec ) on the microsomes and placing on ice for 1 min in between . this ensures that the microsomes are open to penetration by reagents [ 5 ] . the activity was calculated according to eqn 1 : enzyme ⁢ ⁢ activity ⁢ ⁢ ( μ ⁢ ⁢ mol / l / min ) = sample ⁢ - ⁢ blank 10 . 6 ( abs ⁢ ⁢ coefficient ) eqn ⁢ ⁢ 1 table 2 shows the compounds with numbering and the amount of aspirin as a percentage of the initial ester concentration in moles measured at peak aspirin production following addition of candidate esters to buffered human plasma at 37 ° c . at ph 7 . 4 ( phosphate buffer ). half - life and molar % aspirin released in 10 % human plasma half - life and molar % aspirin released in 50 % human plasma 2 . 17 min 46 . 02 % 0 . 83 min 58 . 53 % 4 . 90 min 72 . 23 % 1 . 14 min 85 . 56 % 9 . 72 min 38 . 54 % 1 . 21 ( min ) 53 . 66 % 3 . 63 min 1 . 17 % 0 . 57 ( min ) 1 . 19 % 3 . 76 min 6 . 82 % 0 . 66 ( min ) 6 . 71 % 3 . 32 min 18 . 93 % 0 . 64 ( min ) 28 . 51 % 1 . 29 min 27 . 58 % 0 . 37 ( min ) 17 . 92 % 3 . 68 min 18 . 76 % 0 . 33 ( min ) 27 . 62 % 20 . 63 min 12 . 87 % 4 . 27 ( min ) 18 . 89 % 50 . 22 min 2 . 82 % 1 . 55 ( min ) 4 . 68 % 3 . 59 min 5 . 16 % 0 . 99 ( min ) 7 . 08 % 3 . 28 min 18 . 91 % 0 . 85 ( min ) 17 . 00 % 3 . 17 min 2 . 53 % 1 . 10 ( min ) 3 . 75 % 6 . 23 min 15 . 85 % 2 . 16 ( min ) 14 . 49 % 2 . 86 min 18 . 46 % 1 . 37 ( min ) 22 . 25 % 4 . 43 min 51 . 0 % 0 . 68 ( min ) 60 . 47 % unsubstituted , r = h ( isosorbide - 2 - 4 . 08 min 2 . 95 % not tested not tested aspirinate ) 17 1 . 85 min 74 . 2 % n / a n / a 1 . 9 min & lt ; 2 % n / a n / a not tested not tested 4 . 3 min & lt ; 1 % not tested not tested & gt ; 1 hour & lt ; 1 % not tested not tested 1 . 4 min 45 % not tested not tested 2 . 7 min 48 % not tested not tested 3 . 1 min & lt ; 1 % not tested not tested & lt ; 1 min 72 % not tested not tested & lt ; 1 min 68 % not tested not tested 4 . 1 min & lt ; 1 % not tested not tested 1 . 3 min 21 % not tested not tested & gt ; 5 min & lt ; 1 % not tested not tested 2 . 5 min & lt ; 1 % not tested not tested 3 . 2 min 81 % not tested not tested 2 . 7 min 78 % 5 . 99 min 2 % not tested not tested 3 . 61 min & lt ; 0 . 5 % not tested not tested qualitative hydrolysis screening of is - 2 - aspirinate - 5 - salicylate 2 ( 0 . 1 mm ) was studied using guinea pig , hamster , rabbit and monkey plasma . the purpose of this test was to determine a suitable species for biological testing and preclinical development . the results were also expected to confirm the role of the human enzymes already identified because these are variously distributed in laboratory animals . once a gradient method was successfully developed hydrolysis of 2 in 50 % rabbit plasma was run as the rabbit is a potential model for platelet aggregation studies . the ellman assay revealed bche activity at 1 . 1 μmol / l / min . the results suggest that hamster and monkey would make suitable candidates for preclinical testing . since plasma from these species has similar levels of buche to humans the role of that enzyme in human metabolism is also supported . hydrolysis results for is - 2 - aspirinate - 5 - salicylate , isas ( 2 ) in the presence of intestinal or liver microsomes hydrolysis studies in human blood plasma had indicated that isas ( 2 ) is a successful aspirin pro - drug . this work aimed to broaden the analysis to include liver and intestinal microsomal preparations in order to assess how much aspirin release would occur in other tissues during the absorption phase principally at the gastric epithelium and later in the liver . when the drug was incubated in the presence of human liver microsomes and human intestinal microsomes 9 μm and 56 μm of aspirin were produced ( fig1 ) and ( fig1 ) respectively . this raised the question as to whether this was due to the presence of bche or to some other enzyme ( s ) because whereas human blood contains only butyrylcholinesterase the liver and intestinal epithelium also contain carboxylesterases ( ce )— mainly ce - 1 in the liver and ce - 2 in the intestine . the microsomal preparations was therefore pre - incubated with iso - ompa an established bche inhibitor prior to addition of the pro - drug so as to allow sufficient time to inhibit any bche that might have been present in the microsomal preparations . hydrolysis assays were then carried out as previously described to see what effect if any there was on aspirin production . the use of the specific bche inhibitor did not diminish aspirin production suggesting that some other enzyme is involved . the ellman assay was performed on both microsomal preparations so as to determine what levels of bche are present , if any . only minimal amounts were found ( table 3 . 1 ) and could not be attributed to the high levels of aspirin production . bnpp a know carboxylesterase inhibitor was incubated with him and hlm for 10 mins prior to addition of the drug so as to knock out carboxylesterase activity . a marked decrease in aspirin production was seen and after 60 mins the drug had not disappeared . it can be concluded that isas is a substrate for ce - 1 and ce - 2 as well as buche . these enzymes belong to the same family but have marked difference in substrate specificity . for example the ce enzymes are inefficient in the hydrolysis of positively charged substrates such as those favoured by buche , including choline esters . these enzymes are not normally grouped together . surprisingly in the case of isas , ce - 2 present in the him preparations exhibits the same specificity and efficiency as buche and is as good a vector for aspirin release . the result indicates that more than one enzyme is capable of releasing aspirin from the compounds . the hydrolysis of two non - isosorbide based aspirin esters i . e ., 2 - methoxyphenyl - 2 - acetoxybenzoate ( guaicol ester ) and 2 - acetoxybenzoic acid phenyl ester was evaluated in human intestinal microsomes ( 40 μg / ml ). neither of these esters acts as an aspirin prodrug in human plasma i . e . human plasma esterase action does not cause the release of aspirin from these esters . the phenyl aspirinates produced negligible amounts of aspirin in contact with human intestinal microsomes , illustrating that for these substrates the ce - 2 preference is slightly different to buche , in the presence of which hydrolysis occurs without the evolution of aspirin . however , relative to isas and the nitroxymethyl analogues there was little aspirin production . in other words these compounds are not aspirin prodrugs in human plasma and are inefficient aspirin prodrugs in the presence of ce - 2 . the data illustrates that the interaction between ce - 2 and the prodrugs of the invention is special in that effective aspirin production occurs . tesei a , ricotti l , ulivi p , medri l , amadori d , oli w . tesei a et al . 2003 . ncx 4016 , a nitric oxide - releasing aspirin derivative , exhibits a significant antiproliferative effect and alters cell cycle progression in human colon adenocarcinoma cell lines . 2003 . int j oncol 22 ( 6 ): 1297 - 302 . gilmer j . f . et al 2003 , pharm . pharmacol . 55 , 10 , 1351 - 7 . velzquez c , praveen rao p n , knaus e e . 2005 . j med chem . 2005 jun . 16 ; 48 ( 12 ): 4061 - 7 . novel nonsteroidal antiinflammatory drugs possessing a nitric oxide donor diazen - 1 - ium - 1 , 2 - diolate moiety : design , synthesis , biological evaluation , and nitric oxide release studies . j med chem . june 16 ; 48 ( 12 ): 4061 - 7 . walker j , robinson j , stewart j , jacob s . 2007 does enteric - coated aspirin result in a lower incidence of gastrointestinal complications compared to normal aspirin interact cardiovasc thorac surg . august ; 6 ( 4 ): 519 - 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