Patent Application: US-63529403-A

Abstract:
halogenated carboxylic ester derivatives of phenylethyl imidazole , and their method of preparation are disclosed . radio - halogenated forms of these compounds are ideally suited for positron - imaging of the adrenal glands , as it is known that these compounds demonstrate a selective and high rate of accumulation in the adrenals . the method of preparing these derivatives proceeds by the conversion of a stable , non - radioactive intermediate having trialkylstannyl leaving groups . these intermediates are efficiently converted to the corresponding halogenated forms by substitution of the trialkylstannyl group with the halogen or radiohalogen .

Description:
r 1 represents a straight or branched alkyl chain containing from 1 to 4 carbon atoms , wherein the alkyl group is optionally substituted with a halogen ; r 2 represents a straight alkyl chain in ( r )- configuration containing from 1 to 2 carbon atoms ; x denotes a halogen or a radiohalogen ; as used herein , the expression “ alkyl ,” includes methyl and ethyl groups , and straight - chained or branched propyl groups . particular alkyl groups are methyl , ethyl , 2 - fluoroethyl , n - propyl , and isopropyl , especially methyl and ethyl . the term “ halogen ” as used herein , includes iodine , bromine and fluorine , especially iodine . the compound of formula ( i ) in accordance with the present invention is suitably a halogenated derivative of formula ia , and a radiolabelled derivative of formula ib : r 1 and r 2 are as defined above ; x denotes a halogen resp . radioiodine ; preferred are compounds of formula ( ib ), wherein r 1 and r 2 is methyl and x is 123i or 131 i , namely ( r )- 3 -[ 1 -( 4 -[ 123 i ] iodophenyl ) ethyl - 3h - imidazole - 4 - carboxylic acid methyl ester ( 123 i - mto ) and ( r )- 3 -[ 1 -( 4 -[ 131 i ] iodophenyl ) ethyl ]- 3h - imidazole - 4 - carboxylic acid methyl ester ( 131 i - mto ); and wherein r 1 is ethyl , r 2 is methyl and x is 123 i or 131 i , namely ( r )- 3 -[ 1 -( 4 -[ 123 i ] iodophenyl ) ethyl - 3h - imidazole - 4 - carboxylic acid acid ethyl ester ( 123 i - eto ) and ( r )- 3 -[ 1 -( 4 -[ 131 i ] iodophenyl ) ethyl ]- 3h - imidazole - 4 - carboxylic acid ethyl ester ( 131 i - eto ). the present invention includes within its scope stannylated derivatives of formula ii : the stannylated precursors are prepared from the respective halogenated compounds of formula ia to give iia : compounds of formula ii contain a leaving group l , suitably selected from trimethylstannyl , triethylstannyl , tri - n - propylstannyl and tri - n - butylstannyl , especially trimethylstannyl . compounds of formula iia are key intermediates for radiotracer synthesis by oxidative radiohalogenido destannylation . the trialkylstannyl groups in an aromatic ring can be replaced easily by radiohalogen to yield the respective radioactively labelled compounds of formula ( ib ). the invention concerns a process of synthesizing compounds of formula ( i ) by a stereoselective and regioselective new approach . the compounds according to the invention may be prepared by a process which comprises coupling a compound of formula iii : r 2 represents a straight alkyl chain in ( s )- configuration containing from 1 to 2 carbon atoms ; x represents a halogen ; with a compound of formula iv : r 1 represents a straight or branched alkyl chain containing from 1 to 4 carbon atoms , wherein the alkyl group is optionally substituted with a halogen ; the reaction between compounds iii and iv proceeds with inversion of configuration , to give compounds of formula i : r 1 represents a straight or branched alkyl chain containing from 1 to 4 carbon atoms ; r 2 represents a straight alkyl chain in ( r )- configuration containing from 1 to 2 carbon atoms ; x represents a halogen ; particular alkyl groups are methyl , ethyl , 2 - fluoroethyl , n - propyl , and isopropyl , especially methyl and ethyl . the reaction between compounds iii and iv is based on the known mitsunobu reaction ( mitsunobu , 1981 ). the alcohol ( s )- 1 -( 4 - iodophenyl ) ethanol ( iii ) is reacted with methyl imidazole - 4 - carboxylate ( iv ) in the presence of triphenylphosphane and a dialkyl azodicarboxylate ( preferably di - t - butyl azodicarboxylate ). triphenyl phosphinoxide and the hydrazo ester are by - products of the reaction . the reaction conditions favour activation of the alcohol to generate the reactive alkoxyphosphonium salt . methyl imidazole - 4 - carboxylate is expected to be deprotonated , thus n - 1 and n - 3 could react as nucleophile with the alkoxyphosphonium cation to give a mixture of two isomeric n - substituted imidazoles . yet , when coupling iii and iv at low temperature , alkylation is observed exclusively at n - 3 with clean inversion . previous attempts to react secondary alcohols ( alkylaryl or diaryl carbinols ) with symmetrical imidazole - 4 , 5 - dinitrile produced partial resp . complete racemization by the mitsunobu reaction ( botta et al ., 1994 ; corelli et al ., 1995 ). ( s )- iii is a key intermediate and needs to be synthesized ; methyl imidazole - 4 - carboxylate iv is commercially available . since not commercially available , the starting material of formula iii is prepared by a novel synthetic approach , described hereafter and in scheme 1 : starting from 4 - iodophenyl methyl ketone , which is reduced to the racemic alcohol and converted to (±)- 1 -( 4 - iodophenyl ) ethyl chloroacetate , the racemic ester is subjected to stereoselective enzyme hydrolysis . the remaining ( s )- isomer of the ester is separated from the ( r )- alcohol and transesterified to give ( s )- 1 -( 4 - iodophenyl ) ethanol ( ee & gt ; 98 %) iii . laumen & amp ; schneider ( 1988 ) reported that lipase sam ii hydrolyses acetates and chloroacetates of secondary benzyl alcohols with high enantioselectivity , therefore , schneider &# 39 ; s procedure is applied to the resolution of racemic 1 -( 4 - iodophenyl ) ethanol . lipase sam ii is known to hydrolyse preferentially the ( r )- esters of secondary benzyl alcohols ; however , application with the substrate described in the invention is new . ( r )- 4 - iodo - metomidate is derived exclusively from the ( s )- alcohol of the ester which is not accepted as substrate by lipase sam ii . coupling of ( s )- 1 -( 4 - iodophenyl ) ethanol with methyl imidazole - 4 - carboxylate yields ( r )- 4 - iodo - metomidate with clean inversion . this novel reaction offers a versatile approach to the synthesis of compounds described by formula i . ( s )- 1 -( 4 - iodophenyl ) ethanol ( ee & gt ; 98 %) iii is synthesized by lipase - catalysed resolution and coupled with methyl 4 - imidazole carboxylate iv . the two fragments are joined regioselectively at n - 3 with clean inversion of configuration producing ( r )- methyl 3 -[ 1 -( 4 - iodophenyl ) ethyl ]- 3h - imidazole - 4 - carboxylate ( 4 - iodo - mto ) ia . finally , 4 - iodo - metomidate is transformed to the 4 - trimethylstannyl derivative iia to serve as a precursor for labelling eto and mto with radiohalogen ib . compounds of formula ii wherein l represents a leaving group , may be prepared by standard stannylation techniques . the exchange of x ( iodine ) for the trialkylstannyl substituent ( l ) is catalysed by tetrakis ( triphenylphosphane ) palladium to give a stannylated compound of formula iia . radiohalogenated compounds of formula ib are conveniently prepared by reacting a compound of formula iia with radiohalogen ( lodine - 123 ; iodine - 131 ) in the presence of an oxidizing agent , at room temperature . the radioligand 131 i - mto is produced with a specific activity of 1 mbq / nmol , resp . 27 . 3 μci / nmol . the following examples illustrate the preparation of compounds according to the invention . the compounds in accordance with the present invention potently and selectively bind to adrenocortical membranes ( cytochrome p - 450 β - hydroxylase ). whole adrenals from adult male wistar rats were homogenized in 10 mm k 2 hpo 4 / 10 mm hepes ( ph 7 . 1 ) with a glass / teflon piston ( potter - type ). the homogenate was centrifuged at 35 . 000 × g for 10 min , the pellet was resuspended in fresh buffer and centrifuged again . membranes were washed 2 more times and stored as aliquots at − 80 ° c . glass vials containing 0 . 5 ml of 10 mm k 2 hpo 4 / 10 mm hepes , 150 mm nacl ( ph 7 . 1 ), 20 . 000 – 40 . 000 cpm [ 131 i ] mto together with 2 nm 4 - iodo - mto as carrier ( i . e . 1 pmol / vial , resulting in a specific activity of 9 – 18 ci / mmol ), and the adrenal membrane suspension corresponding to 0 . 2 mg tissue / vial , were immersed in a 23 ° c . water bath for 20 – 30 min . after incubation , membranes with bound radioligand were isolated by filtration through whatman gf / b glass fiber filters ( presoaked in buffer ), followed by 2 × 4 ml washings with buffer , then filters were measured in a gamma - spectrometer . the association time course of [ 131 i ] mto to rat adrenal membranes was evaluated at three ligand concentrations , namely 2 nm , 4 nm , and 11 nm of 4 - iodo - mto , respectively ( data pooled from 7 experiments ). computerized curve fitting to the association function b ( t )= b 0 . [ 1 + exp (− v . t )] resulted in observable association rate constants of v = 0 . 65 min − 1 , 1 . 23 min − 1 , and 1 . 34 min − 1 corresponding to association half - times from 30 to 60 seconds . for dissociation experiments , membranes were fully equilibrated with 2 nm radioligand , and the dissociation was initiated by the addition of excess unlabelled 4 - iodo - mto and stepwise filtration at 15 sec intervals . four individual experiments demonstrated fast reversibility of binding and resulted in a dissociation constant of b = 0 . 33 ± 0 . 05 min − 1 and derived dissociation half - times from 1 . 8 to 2 . 4 min . for saturation studies 2 – 100 nm 4 - iodo - mto carrier was used . see summary in fig1 . saturation analysis of [ 131 i ] mto binding to rat adrenal membranes ( 4 representative experiments ) produced 15 linear eadie - hofstee plots suggesting a single binding site . k d = 7 . 4 ± 2 . 8 nm ( 15 ); b max = 2 . 4 ± 0 . 4 pmol / mg tissue ( 15 ). incubation for 30 minutes using 10 mm k 2 hpo 4 / 10 mm hepes , 150 mm nacl ( ph 7 . 1 ). 0 . 2 mg tissue bind ˜ 10 % of the free ligand ( 0 . 1 pmol ). compounds of formula i and derivatives were evaluated as competitive inhibitors of [ 131 i ] mto binding . test compounds were incubated at 0 . 01 – 100 nm concentrations . non - specific binding was determined with etomidate ( 10 μm ). the reaction was initiated by the addition of membrane and was terminated by filtration through whatman gf / b filters ( presoaked in buffer ), followed by 2 × 4 ml washings with buffer . the filters containing membranes with bound radioligand were measured in a gamma - spectrometer . ic 50 values ( the molar concentration of compound necessary to inhibit binding by 50 %) were determined for each test compound by non - linear , least squares regression analysis , using an iterative curve fitting routine . the ic 50 values for binding to the cytochrome p - 450 11β enzyme system obtained for derivatives of etomidate resp . metomidate of the accompanying examples were below 10 nm in each case . moreover , it was demonstrated that ( r )- configuration of the methyl substituent at the chiral c - atom is essential for binding , ( s )- configuration is not tolerated ( ic 50 = 492 nm ); cleavage of the ester results in deactivation , the free acid ( eto - acid ) is inactive ( ic 50 = 123 μm ); modification of the ester by 2 - fluoroethyl ( feto ) is tolerated without a loss of affinity ( ic 50 = 3 . 0 nm ); the ethyl ester ( etomidate ) shows the highest potency ( ic 50 = 1 . 1 nm ); the methyl ester ( metomidate ; ic 50 = 3 . 7 nm ) and 4 - iodo - mto ( ic 50 = 9 . 0 nm ) show similar potencies . metyrapone , a known , clinically used inhibitor , showed micromolar potency ( ic 50 = 1 . 2 μm ) when tested in this assay . in vivo evaluation of 131 i - mto ( fig3 , 4 ) method : 131 i - mto was used with a radiochemical purity & gt ; 99 % and a specific activity of 57 gbq / μmol . the radiotracer ( 0 . 5 – 1 . 1 mbq ; 10 – 20 μci ) was injected into the tail vein of rats ( female , 180 – 220 gram ). groups of four rats were sacrifized at specified times up to 24 hours post injection . the organs were excised and weighed , the radioactivity was measured at constant geometry using a gamma - spectrometer with a nal ( ti )- crystal . the data were expressed as percent of injected dose ( id ) per organ and as percent of id per gram tissue . results : 131 i - mto showed high specific uptake in the adrenals of approximately 10 % id / g tissue with a radioactivity plateau for 2 hours . the radiotracer is eliminated both by hepatobiliary and by renal excretion . renal activity is attributed to 131 i - eto - acid , which results from enzymatic cleavage of the methyl ester . the renal activity is increasing up to 4 hours post injection . based on calculations of the target - to - non - target - ratios the highest contrast for imaging of the adrenals is observed up to one hour post injection . thus , [ 131 i ]- i - mto shows a high potential as radiotracer for the functional imaging of adrenal pathology . similar distribution kinetics are demonstrated with 18 f - fluoroetomidate . fig5 . the present invention is described below in more detail in connection with the synthesis of the radiotracer ( r )- 3 -[ 1 -( 4 -[ 131 i ] iodophenyl ) ethyl ]- 3h - imidazole - 4 - carboxylic acid methyl ester ( 131 i - mto ); the example is given merely for illustrative purposes and shall in no way be understood as a limitation of the scope of the present invention which is given by the patent claims . preparation of ( r )- 3 -[ 1 -( 4 -[ 131 i ] iodophenyl ) ethyl ]- 3h - imidazole - 4 - carboxylic acid methyl ester i . e . ( 131 i - mto ); a solution of dibah ( 16 . 45 cm 3 , 24 . 67 mmol , 1 . 5 m solution in toluene ) was added dropwise to a stirred mixture of 4 - iodoacetophenone ( 5 . 08 g , 20 . 65 mmol ) in dry diethyl ether ( 50 cm 3 ) at − 78 ° c . in an atmosphere of argon . after stirring for 2 h at − 78 ° c ., methanol ( 2 cm 3 ) was added and stirring was continued for 30 min at room temperature before water ( 10 cm 3 ) was added cautiously . 30 min later , the aluminum hydroxide formed was dissolved in hydrochloric acid ( 50 cm 3 , 2 m ) under cooling with ice . the organic phase was separated , washed with water and a saturated aqueous solution of sodium hydrogen carbonate , dried ( magnesium sulphate ) and concentrated under reduced pressure . the crude product was purified by flash chromatography ( hexane - dichloromethane 1 : 2 ; r f = 0 . 20 ) on silica gel and bulb to bulb distillation ( 0 . 2 mmhg / 90 – 95 ° c .) to give (±)-( 3 . 91 g , 86 %) as liquid which crystallised ; mp 47 – 49 ° c . ( lit . 50 . 5 – 51 . 5 ° c .). δ h ( 400 . 13 mhz , cdcl 3 ) 1 . 40 ( 3 h , d , j 6 . 5 , ch 3 ch ), 1 . 75 ( 1 h , br s , oh ), 4 . 78 ( 1 h , q , j 6 . 5 , ch 3 ch ), 7 . 06 ( 2 h , d , j 8 . 5 , 2 × h arom ), 7 . 60 ( 2 h , d , j 8 . 5 , 2 × h arom ); δ c ( 100 . 61 mhz , cdcl 3 ) 25 . 62 ( ch 3 ch ), 70 . 25 ( ch 3 ch ), 93 . 09 ( ic arom ), 127 . 79 ( 2 c , 2 × hc arom ), 137 . 94 ( 2 c , 2 × hc arom ), 145 . 86 ( c arom ). dry pyridine ( 6 . 0 cm 3 ) and chloroacetic anhydride ( 6 . 2 g , 36 . 26 mmol ) were added to a stirred solution of (±)- 1 -( 4 - iodophenyl ) ethanol ( 5 . 95 g , 24 . 0 mmol ) in dry dichloromethane ( 100 cm 3 ) at 0 ° c . under an atmosphere of argon . when the reaction was finished ( 2 h , tlc : hexane - dichloromethane 3 : 2 , rf = 0 . 35 for ester ), water ( 40 cm 3 ) and concentrated hydrochloric acid ( 3 . 6 cm 3 ) were added . after stirring for 10 min , the organic phase was separated and the aqueous phase was extracted with dichloromethane ( 3 × 15 cm 3 ). the combined organic phases were washed with water ( 50 cm 3 ) and a saturated solution of sodium hydrogen carbonate ( 25 cm 3 ), dried ( sodium sulfate ) and evaporated under reduced pressure . the residue was purified by flash chromatography ( hexane - dichloromethane 3 : 2 , rf = 0 . 35 ) on silica gel and bulb to bulb distillation ( 0 . 1 mmhg / 105 ° c .) to give chloroacetate ( 7 . 09 g , 91 %) as a colourless liquid ( found : c , 36 . 9 ; h , 3 . 25 , c 10 h 10 clio 2 requires c , 37 . 0 ; h , 3 . 1 %), which crystallised spontaneously ; mp 50 – 51 ° c . ν max ( si , film )/ cm − 1 2983 , 1756 , 1591 , 1488 , 1285 , 1176 , 1063 , 1007 ; δh ( 400 . 13 mhz , cdcl 3 ) 1 . 54 ( 3 h , d , j 7 . 0 , ch 3 ch ), 4 . 03 ( 2 h , d , j 14 . 8 , ch 2 cl ), 5 . 90 ( 1 h , q , j 7 . 0 , ch 3 ch ), 7 , 08 ( 2 h , d , j 8 . 5 , 2 × h arom ), 7 . 68 ( 2 h , d , j 8 . 0 , 2 × h arom ); δ c ( 100 . 61 mhz , cdcl 3 ); 21 . 84 ( ch 3 ch ), 40 . 99 ( ch 2 cl ), 73 . 84 ( ch 3 ch ), 93 . 85 ( ic arom ), 128 . 08 ( 2 c , 2 × hc arom ), 137 . 75 ( 2 c , 2 × hc arom ), 140 . 30 ( c arom ), 166 . 45 ( co ). racemic chloroacetate ( 0 . 835 g , 2 . 57 mmol ) t - butyl methyl ether ( 4 cm 3 ) and phosphate buffer ( 50 mmol , sterile , 17 cm 3 ) and lipase sam ii ( 96 mg ) were stirred vigorously at room temperature . the ph was kept constant at 7 . 0 by addition of 0 . 5 n sodium hydroxide using an autotitrator . 98 % of the calculated amount of base were consumed in 2 . 6 hr . the reaction was stopped after another 14 h ( virtually no base was consumed during the last 9 hr ) by bringing the ph to about 2 . 0 using 2 n hydrochloric acid . water ( 100 cm 3 ) was added and ester and alcohol were extracted with dichloromethane ( 3 × 200 cm 3 ). the combined organic layers were washed with water and a saturated solution of sodium hydrogen carbonate ( 50 cm 3 each ), dried ( sodium sulfate ), and evaporated under reduced pressure to leave a residue which was purified by flash chromatography ( hexane - dichloromethane 3 : 2 for chloroacetate , rf = o0 . 35 ; hexane - dichloromethane 1 : 2 for alcohol , rf = 0 . 20 ) on silica gel to give ( s )- chloroacetate ( 0 . 367 g , 44 %, [ α ] 20 d = 82 . 57 ( c 2 . 57 in acetone ), ee 98 % and [ α ] 20 d =+ 35 . 68 ( c 2 . 04 in acetone ) after chemical hydrolysis ) as a liquid and ( r )- alcohol ( 0 . 393 g , 43 %, ee 98 %; [ α ] 20 d =+ 35 . 92 ( c 1 . 96 in acetone ) before crystallisation from petroleum ether ( 40 – 60 ° c . )- dichloromethane , afterwards [ a ] 20 d =+ 35 . 95 ( c 2 . 05 in acetone ); mp 48 – 49 ° c .) as a crystalline solid . ( s )- chlorocetate ( 0 . 340 g , 1 . 05 mmol ) was dissolved in methanol / sodium methoxide ( 17 cm 3 , obtained by dissolving 69 mg of sodium in 30 cm 3 of dry methanol ). after 1 hr , water ( few drops ) was added and solution was concentrated under reduced pressure . water ( 30 cm 3 ) and dichloromethane ( 15 cm 3 ) were added . the organic layer was separated and the aqueous one was extracted with dichloromethane ( 2 × 15 cm 3 ). the combined organic layers were dried ( sodium sulfate ) and evaporated to leave a residue , which was purified by flash chromatography ( hexane - dichloromethane 1 : 2 , rf = 017 ) to give ( s )- alcohol ( 0 . 240 g , 92 %, ee 98 %) as a crystalline solid . a solution of ( s )- alcohol ( 1 . 98 g , 7 . 98 mmol , ee & gt ; 98 %) in dry thf ( 14 . 5 cm 3 ) was added dropwise to a stirred solution of methyl 3h - imidazole - 4 - carboxylate ( 1 . 008 g , 7 . 98 mmol ) and triphenylphosphane ( 2 . 503 g , 9 . 43 mmol ) in dry thf ( 22 . 0 cm 3 ) in an atmosphere of argon − 30 ° c . then , a solution of di - t - butyl azodicarboxylate ( 2 . 204 g , 9 . 57 mmol ) in dry thf ( 14 . 5 cm 3 ) were added and the stirred reaction mixture was allowed to warm up from − 30 ° c . to 0 ° c . within 2 . 5 hr . no alcohol could by detected by tlc ( diethyl ether - diisopropylamine 10 : 1 ). the reaction mixture was concentrated under reduced pressure . the residue was mixed with diethyl ether ( 36 cm 3 ) and stirred for 2 h . the crystals ( triphenylphosphanoxide and hydrazo ester ) were collected and washed with diethyl ether ( 3 × 15 cm 3 ). the filtrate was evaporated und reduced pressure to leave a residue , which was purified by flash chromatography ( hexanes - diethyl ether - diisopropylamine 50 : 30 : 1 ; tlc : diethyl ether - diisopropylamine 10 : 1 , rf = 0 . 44 for iodide , 0 . 54 for metomidate ) on silica gel to give p - iodo - metomidate ( 1 . 91 g , 67 %, ee 99 %); [ α ] 20 d =+ 76 . 0 ( c 1 . 09 in acetone ). found : c , 43 . 8 ; h , 3 . 7 ; n , 7 . 9 . c 13 h 13 in 2 o 2 requires c , 43 . 7 ; h , 3 . 8 ; n , 7 . 7 ; ν max ( si , film )/ cm − 1 2981 , 2947 , 1712 , 1487 , 1437 , 1363 , 1220 , 1134 , 1111 , 1006 ; δ h ( 400 . 13 mhz , cdcl 3 ) 1 . 81 ( 3 h , d , j 7 . 5 , ch 3 ch ), 3 . 77 ( 3 h , s , och 3 ), 6 . 26 ( 1 h , q , j 7 . 5 , ch 3 ch ), 6 . 88 ( 2 h , d , j 8 . 5 , 2 × h arom ), 7 . 63 ( 2 h , d , j 8 . 5 , 2 × h arom ), 7 . 73 ( 1 h , s h hetarom ), 7 . 75 ( 1h , d , j 1 . 0 , h hetarom ); δ c ( 100 . 61 mhz , cdcl 3 ) 22 . 09 ( ch 3 ch ), 51 . 47 ( och 3 ), 54 . 96 ( ch 3 ch ), 93 . 46 ( ic arom ), 122 . 29 ( 2 c , 2 × hc arom ), 128 . 02 ( 2 c , 2 × hc arom ), 137 . 94 ( c arom ), 138 . 40 ( hc hetarom ), 139 . 54 ( hc hetarom ), 141 . 10 ( cco ), 160 . 58 ( co ). hexamethyiditin ( 0 . 645 g . 3 . 2 mmol , 6 . 5 cm 3 of a solution of 1 . 0 g hexamethylditin in 10 cm 3 of dry toluene ), tetrakis ( triphenylphosphane ) palladium ( 58 mg , 5 mol %) and triethylamine ( 1 . 6 cm 3 , 11 . 6 mmol ) were added to a stirred solution of iodometomidate ( 0 . 368 g . 1 . 03 mmol , ee & gt ; 98 %) in an atmosphere of argon and refluxed ( bath temperature 135 ° c .) for 17 hr . the cooled solution was concentrated under reduced pressure and the residue was purified by flash chromatography ( hexane - diethyl ether - diisopropylamine 60 : 30 : 1 ; tlc : diethyl ether - diisopropylamine 10 : 1 , r f = 0 . 71 for stannane , r f = 0 . 50 for iodometomidate ) on silica gel to give stannane ( 0 . 377 g , 96 %) as a crystalline solid ( found : c , 48 . 7 ; h , 5 . 6 n , 7 . 1 , c 16 h 22 n 2 o 2 sn requires c , 48 . 9 ; h , 5 . 6 ; n , 7 . 1 %); mp 77 – 79 ° c . ( from hexane ); [ α ] 20 d =+ 82 . 09 ( c 2 . 06 in acetone ). ν max ( si , film )/ cm − 1 2981 , 1715 , 1437 , 1362 , 1218 , 1133 , 1110 , 1049 ; δ h ( 400 . 13 mhz , cdcl 3 ) 0 . 25 ( 9 h , s , ( ch 3 ) 3 sn , 117 / 119 sn satellites , 2 × d , j 53 . 2 and 55 . 2 ), 1 . 82 ( 3 h , d , j 7 . 0 , ch 3 ch ), 3 . 77 ( 3 h , s , och 3 ), 6 . 30 ( 1 h , q , j 7 . 0 , ch 3 ch ), 7 . 13 ( 2 h , d , j 8 . 0 , 2 × h arom , 117 / 119 sn satellites , d , j 9 . 0 ), 7 . 43 ( 2 h , d , j 8 . 0 , 2 × h arom , 117 / 119 sn satellites , d , j 42 . 7 ), 7 . 71 ( 1 h , s , h hetarom ), 7 . 74 ( 1 h s , h hetarom ) δ c ( 100 . 61 mhz , cdcl 3 )− 9 . 61 ( 3 c , ( ch 3 ) 3 sn ), 22 . 16 ( ch 3 ch ), 51 . 40 ( och 3 ), 55 . 30 ( ch 3 ch ), 122 . 31 ( c arom ), 125 . 81 ( 2 × c , 2 × hc arom ), 117 / 119 sn satellites , d , j 45 . 9 ), 136 . 28 ( 2 × c , 2 × hc arom , 117 / 119 sn satellites , d , j 36 . 8 ), 122 . 29 ( 2 c , 2 × hc arom ), 128 . 02 ( 2 c , 2 × hc arom ), 137 . 94 ( c arom ), 138 . 23 ( hc hetarom ), 139 . 84 ( hc hetarom ), 141 . 00 ( c arom or cco ), 142 . 24 ( cco or c arom ), 160 . 68 ( co ). 30 μg 4 - stannan - mto is reacted with [ 131 i ] iodide in 10 – 20 μl naoh ( 0 . 05 n ), 15 μl chloramine - t ( 1 mg / ml , aqueous ), 6 μl hydrochloric acid ( 1 n ) during 1 min at ambient temperature . the reaction is stopped with 6 μl naoh ( 1 n ), to give the compound with a radiochemical yield : & gt ; 95 %, radiochemical purity : & gt ; 99 %, specific activity : 1 mbq / nmol ; chemical purity : & gt ; 95 %. by following the preparation as described above for ( r )- methyl 3 -[ 1 -( 4 - iodophenyl ) ethyl ]- 3h - imidazole - 4 - carboxylate ( 4 - iodo - mto ) further compounds according to the invention can be synthesized , such as e . g . 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