text: the present invention will be better understood in the light of the examples which follow , which are provided for illustrative purposes only and in no way limit the scope of the invention . all the reactions were carried out in the open air unless otherwise specified . 1 . 57 g ( 7 . 5 mmol ) of l - histidine hydrochloride monohydrate is dissolved in 15 ml of water and the solution is cooled at 0 ° c . under very strong stirring , 500 μl ( 1 . 56 g , 9 . 75 mmol , 1 . 3 eq ) of bromine is added dropwise ( addition time : 2 min 10 sec ). the reaction mixture turns yellow . three minutes after the end of the addition of bromine , 2 . 81 g ( 22 . 5 mmol , 3 eq ) of l - cysteine is added . immediately , the mixture loses its color . after stirring at 0 ° c . for 1 hour , the mixture is filtered and the precipitate is washed with 2 × 0 . 5 ml of water . the filtrate is deposited on a column filled with 75 g of dowex ® 50wx2 - 400 , conditioned beforehand with 1 n hydrochloric acid ( hcl ). after elution with 750 ml of 1 n hydrochloric acid and then 500 ml of 2 n hydrochloric acid , the fractions containing the desired product are combined . after evaporation and two co - evaporations with 2 × 20 ml of toluene , 1 . 5 g ( 56 %) of the desired product in the form of yellow crystals is obtained after drying . 1 h - nmr ( d 2 o / dcl , 400 mhz ): δ ( ppm )= 3 . 32 ( m , 2h ); 3 . 63 ( m , 2h ); 4 . 22 ( m , 2h ); 7 . 39 ( s , 1h ). 4 . 753 g ( 20 mmol ) of n , n - dimethylhistidine hydrochloride monohydrate ( v . n . reinhold et al ., j . med . chem . 11 , 258 ( 1968 )) is dissolved in 40 ml of water and the solution is cooled at 0 ° c . under very strong stirring , 1 . 23 ml ( 3 . 835 g , 24 mmol , 1 . 2 eq ) of bromine is rapidly added dropwise ( addition time : 1 min 20 sec ), without exceeding 2 ° c . the reaction mixture turns yellow and a reddish solid is formed . seven minutes after the end of the addition of bromine , all the red solid dissolves and then 7 . 417 g ( 60 mmol , 3 eq ) of l - cysteine is added . immediately , the mixture loses its color . after stirring at 0 ° c . for 1 hour , a white suspension is obtained . the mixture is filtered and the precipitate is washed with 2 × 2 ml of water . the filtrate is deposited on a column filled with 100 g of dowex ® 50wx2 - 400 , conditioned beforehand with 1 n hydrochloric acid ( hcl ). after elution with 800 ml of 1 n hydrochloric acid and then 1000 ml of 2 n hydrochloric acid , the fractions containing the desired product are combined . after evaporation and two co - evaporations with 2 × 50 ml of toluene , 4 . 84 g ( 63 %) of the desired product in the form of slightly yellow crystals is obtained after drying . 1 h - nmr ( d 2 o , 400 mhz ): δ ( ppm )= 2 . 86 ( s , 6h ); 3 . 32 ( m , 2h ); 3 . 61 ( m , 2h ); 4 . 21 ( m , 1h ); 4 . 32 ( m , 1h ); 7 . 37 ( s , 1h ). 1 . 187 g ( 5 . 656 mmol ) of α - n - methylhistidine hydrochloride ( v . n . reinhold et al ., j . med . chem . 11 , 258 ( 1968 )) is dissolved in 11 . 3 ml of demineralized water . the solution is cooled at 0 ° c . and 377 μl ( 1 . 175 g , 7 . 353 mmol , 1 . 3 eq ) of bromine is added dropwise under very strong stirring ( addition time : 1 min 45 sec ). the reaction mixture turns yellow and the temperature increases to 4 ° c . three minutes after the end of the addition of bromine , 2 . 119 g ( 16 . 96 mmol , 3 eq ) of l - cysteine is added . immediately , the mixture loses its color . after stirring at 0 ° c . for 1 hour , the mixture is deposited on a column filled with 50 g of dowex ® 50wx2 - 400 , conditioned beforehand with 0 . 5 n hydrochloric acid . after elution with 250 ml of 0 . 5 n hydrochloric acid and then 250 ml of 1 n hydrochloric acid and 500 ml of 1 . 5 n hydrochloric acid , the fractions containing the desired product are combined . after evaporation and drying under vacuum ( 20 mbar ), 1 . 427 g ( 68 %) of the desired product in the form of yellow crystals is obtained . 1 h - nmr ( d 2 o , 400 mhz ): δ ( ppm )= 2 . 71 ( s , 3h ); 3 . 33 ( m , 2h ); 3 . 62 ( m , 2h ); 4 . 08 ( m , 1h ); 4 . 28 ( m , 1h ); 7 . 40 ( s , 1h ). 2 — preparation of compounds of the formula ( i ) of the invention ( without isolation of the intermediates of the formula ( ii )) 317 . 6 g ( 1 . 5 mol ) of l - histidine hydrochloride monohydrate is dissolved in 3 liters of demineralized water . the solution is transferred to a double - walled glass reactor with mechanical stirring and is cooled at − 4 ° c . under very strong stirring , 100 . 2 ml ( 311 . 6 g , 1 . 95 mol , 1 . 3 eq ) of bromine is added very quickly via a bromine vial , without exceeding 4 ° c . ( addition time : 2 min 50 sec ). the reaction mixture turns yellow - orange but remains clear and homogeneous . three minutes after the end of the addition of bromine , 562 g ( 4 . 5 mol , 3 eq ) of l - cysteine is added and the internal temperature increases to 12 ° c . immediately , the mixture loses its color . after several minutes the solution becomes slightly yellow . c after stirring at 0 ° c . for 1 hour , analysis of a sample by 1 h - nmr ( d 2 o ) shows that the his - cys adduct is formed with a reaction yield of 70 %. the cooling system is turned off and the reaction mixture is allowed to stir for 1 hour . the internal temperature increases to 12 ° c . the his - cys adduct is not isolated and is engaged directly in the following step . 793 . 4 ml ( 960 g , 9 mol , 6 eq ) of 3 - mercaptopropionic acid is then added to the mixture , which is then heated under strong stirring at 100 ° c . for 18 h . analysis of a sample by 1 h - nmr ( d 2 o ) shows that the his - cys adduct is completely cleaved into l - 2 - thiohistidine . after cooling at room temperature , the dark - brown mixture is extracted with 4 × 3 l of ethyl acetate . the aqueous phase is retained and placed under a strong stream of nitrogen in a 40 ° c . bath . the ph of the mixture is adjusted to 8 . 5 by rapidly adding 20 % aqueous ammonia solution ( roughly 580 ml ). still under nitrogen , 37 % concentrated hydrochloric acid is then added dropwise ( roughly 120 ml ) until a ph of 6 . 5 is reached . a colorless precipitate forms during the addition of the acid , and the suspension is maintained for 1 hour at 40 ° c . under stirring ( under nitrogen ). after filtration and washing with 3 × 300 ml of demineralized water , followed by 2 washings with 600 ml of absolute ethanol and 3 × 600 ml of n - pentane , the solid obtained is dried over p 2 o 5 under vacuum ( 20 mbar ). 130 . 1 g ( 45 %) of l - 2 - thiohistidine in the form of a white powder is obtained . the analytical data of the product obtained are identical to those in the literature ( j . xu , j . c . yadan , j . org . chem . 60 , 6296 - 6301 ( 1995 )). 1 h - nmr ( d 2 o / dcl , 400 mhz ): δ ( ppm )= 3 . 10 ( m , 2h ); 4 . 20 ( m , 1h ); 6 . 77 ( s , 1h ). the following examples 5 to 8 show the variability of the acid addition salt of the compound of the formula ( iii ) which can be used , as well as the variability of the thiol which can be used . these examples are for illustrative purposes only and in no way limit the scope of the present invention . the procedure is as described in example 2 , except that 5 g ( 32 . 2 mmol ) of l - histidine is used , dissolved in 65 ml of water and 900 μl ( 1 . 66 g , 16 . 1 mmol , 1 eq ) of 98 % sulfuric acid . 2 . 72 g ( 45 %) of l - 2 - thiohistidine in the form of a white powder is obtained . 1 h - nmr ( d 2 o / dcl ) analysis is identical to that described in example 1 . 3 . 5 g ( 16 . 52 mmol ) of l - histidine hydrochloride monohydrate is dissolved in 33 ml of water and the solution is cooled at − 3 ° c . under very strong stirring , 1 . 1 ml ( 3 . 433 g , 21 . 48 mmol , 1 . 3 eq ) of bromine is rapidly added dropwise ( addition time : 3 min ). the reaction mixture turns yellow . three minutes after the end of the addition of bromine , 6 . 19 g ( 49 . 58 mmol , 3 eq ) of l - cysteine is added . immediately , the mixture loses its color . after stirring at 0 ° c . for 30 min , 7 . 13 ml ( 9 . 4 g , 99 . 17 mmol ) of mercaptoacetic acid is added and then the solution while stirring is heated at 80 ° c . for 40 h . for the isolation of l - 2 - thiohistidine , the procedure is as described in example 1 . 43 % of l - 2 - thiohistidine in the form of a cream - white powder is obtained . 1 h - nmr ( d 2 o / dcl ) analysis is identical to that described in example 1 . 257 mg ( 1 . 21 mmol ) of l - histidine hydrochloride monohydrate is dissolved in 2 . 4 ml of water and the solution is cooled at − 3 ° c . under very strong stirring , 80 μl ( 252 mg , 1 . 58 mmol , 1 . 3 eq ) of bromine is rapidly added dropwise . the reaction mixture turns yellow . three minutes after the end of the addition of bromine , 455 mg ( 3 . 64 mmol , 3 eq ) of l - cysteine is added . immediately , the mixture loses its color . after stirring at 0 ° c . for 1 hour , 933 μl ( 1 . 0 g , 6 . 07 mmol ) of mercaptohexanoic acid is added and then the solution while stirring is heated at 80 ° c . for 40 h . 1 h - nmr ( d 2 o ) analysis of a sample shows that the his - cys adduct is completely cleaved into l - 2 - thiohistidine . 10 . 72 g ( 50 . 62 mmol ) of l - histidine hydrochloride monohydrate is dissolved in 100 ml of water and the solution is cooled at 0 ° c . under very strong stirring , 3 . 38 ml ( 10 . 51 g , 65 . 81 mmol , 1 . 3 eq ) of bromine is rapidly added dropwise ( addition time : 3 min 20 sec ) without exceeding 1 ° c . the reaction mixture turns yellow . three minutes after the end of the addition of bromine , 18 . 96 g ( 151 . 8 mmol , 3 eq ) of l - cysteine is added . immediately , the mixture loses its color . after stirring at 0 ° c . for 1 hour , 47 . 08 g ( 303 . 7 mmol , 6 eq ) of dithiothreitol is added , and then the solution while stirring is heated at 80 ° c . for 40 h . for the isolation of l - 2 - thiohistidine , the procedure is as described in example 1 . 41 % of l - 2 - thiohistidine in the form of a white powder is obtained . 1 h - nmr ( d 2 o / dcl ) analysis is identical to that described in example 1 . the procedure is as described in example 2 - 1 , except that 10 . 32 g ( 65 . 84 mmol ) of d - histidine is used , dissolved in 132 ml of water and 5 . 5 ml ( 6 . 48 g , 65 . 84 mmol ) of concentrated hydrochloric acid . 4 . 4 g ( 35 %) of d - 2 - thiohistidine in the form of a white powder is obtained . 1 h - nmr ( d 2 o / dcl ) analysis is identical to that described in example 1 . 10 . 65 g ( 50 . 8 mmol ) of d , l - histidine hydrochloride monohydrate is dissolved in 100 ml of demineralized water . the solution is cooled at − 3 ° c . under very strong stirring , 3 . 43 ml ( 10 . 66 g , 66 mmol , 1 . 3 eq ) of bromine is added very quickly via a bromine vial , without exceeding 1 ° c . ( addition time : 2 min 40 sec ). the reaction mixture turns yellow - orange but remains clear and homogeneous . three minutes after the end of the addition of bromine , 19 . 03 g ( 152 . 4 mol , 3 eq ) of l - cysteine is added and the internal temperature increases to 4 ° c . immediately , the mixture loses its color . after several minutes the solution becomes slightly yellow . after stirring at 0 ° c . for 1 hour , analysis by 1 h - nmr ( d 2 o ) of a sample shows that the his - cys adduct is formed with a reaction yield of 72 %. the cooling bath is removed and the reaction mixture is allowed to stir for 30 min . the internal temperature increases to 10 ° c . 27 ml ( 32 . 68 g , 304 . 8 mol , 6 eq ) of 3 - mercaptopropionic acid is then added to the mixture , which is then heated under strong stirring at 80 ° c . for 30 h . analysis of a sample by 1 h - nmr ( d 2 o ) shows that the his - cys adduct is completely cleaved into 2 - thiohistidine . after cooling at room temperature , the dark - brown mixture is extracted with 4 × 100 ml of ethyl acetate . the aqueous phase is retained and placed under a strong stream of nitrogen in a 40 ° c . bath . the ph of the mixture is adjusted to 6 by quickly adding 20 % aqueous ammonia solution . a colorless precipitate is formed , and the suspension is maintained for 25 min at 40 ° c . under stirring ( under nitrogen ). after filtration and washing with 3 × 15 ml of demineralized water , followed by 2 washings with 15 ml of absolute ethanol and 3 × 15 ml of n - pentane , the solid obtained is dried over p 2 o 5 under vacuum ( 20 mbar ). 5 . 2 g of d , l - 2 - thiohistidine in the form of a white powder , containing roughly 10 % cysteine , is obtained . the product is purified by an acid - base treatment : 585 mg ( 3 . 79 mmol ) of dithiothreitol is dissolved in 100 ml of demineralized water and then the product previously obtained ( 5 . 2 g ) is added . the suspension is placed under nitrogen in a 40 ° c . water bath and 10 ml ( 11 . 84 g ) of concentrated hydrochloric acid is added very slowly dropwise until the solid dissolves completely . the ph is then adjusted to 6 by the slow addition of 3 ml ( 2 . 735 g ) of 20 % aqueous ammonia solution . a fine colorless precipitate slowly forms and the suspension is maintained under stirring for 1 hour . after filtration and washing with 3 × 10 ml of demineralized water followed by 3 washings with 10 ml of absolute ethanol and 3 × 10 ml of n - pentane , the solid obtained is dried over p 2 o 5 under vacuum ( 20 mbar ). 3 . 82 g ( 39 %) of d , l - 2 - thiohistidine in the form of a white powder is obtained . 1 h - nmr ( d 2 o / dcl ) analysis is identical to that described in example 1 . a ) preparation of the hisnme 2 - cys adduct ( compound of the formula ( ii )) 23 . 76 g ( 0 . 1 mol ) of α , α - dimethylhistidine hydrochloride monohydrate ( v . n . reinhold et al ., j . med . chem . 11 , 258 ( 1968 )) is dissolved in 200 ml of water . the solution is cooled at − 3 ° c ., and under very strong stirring 6 . 68 ml ( 20 . 77 g , 130 mmol , 1 . 3 eq ) of bromine is added quickly dropwise without exceeding 3 ° c . ( addition time : 4 min ). the reaction mixture turns yellow and a reddish solid is formed . seven minutes after the end of the addition of bromine the red solid completely dissolves and 37 . 08 g ( 0 . 3 mol , 3 eq ) of l - cysteine is added . the internal temperature rises from 0 ° c . to 1 ° c . and the mixture immediately loses its color . after stirring at 0 ° c . for 1 hour , analysis of a sample by 1 h - nmr ( d 2 o ) shows that the his nme 2 - cys adduct forms with a reaction yield of 63 %. the ice bath is removed and the reaction mixture is allowed to stir for 1 hour . the internal temperature increases to 10 ° c . 87 . 7 ml ( 106 g , 10 eq ) of 3 - mercaptopropionic acid is then added to the mixture , which is heated under strong stirring at 80 ° c . for 24 h . analysis of a sample by 1 h - nmr ( d 2 o ) shows that the his nme 2 - cys product is cleaved completely . after cooling at room temperature , the orange mixture is extracted with 4 × 400 ml of ethyl acetate . the aqueous phase is retained and the ph is adjusted to 4 . 5 - 5 with 20 % aqueous ammonia solution ( roughly 21 ml ). in order to trap the excess cysteine present in the medium , 30 . 5 ml ( 31 . 8 g , 3 eq ) of benzaldehyde is added ( according to m . p . schubert , j . biol . chem . 114 , 341 - 350 ( 1936 ) or m . seki et al ., j . org . chem . 67 ( 16 ), 5532 ( 2002 )). the mixture is stirred at room temperature for 15 h and 2 - phenylthiazolidine - 4 - carboxylic acid precipitates in the form of a light yellow solid . after filtration of the solid and rinsing with 4 × 40 ml of water , the filtrate is extracted with 2 × 200 ml of ethyl acetate . the aqueous phase is retained and the ph is adjusted to 6 with 20 % aqueous ammonia solution ( roughly 2 ml ). the mixture is then evaporated dry and the solid obtained is recrystallized in water . 7 . 28 g ( 33 %) of the desired product in the form of a white powder is obtained . the analytical data are identical to those described in the literature ( wo 95 / 18108 ). 1 h - nmr ( d 2 o / dcl , 400 mhz ): δ ( ppm )= 2 . 87 ( s , 6h ); 3 . 20 ( m , 2h ); 4 . 19 ( m , 1h ); 6 . 78 ( s , 1h ). 11 . 93 g ( 54 . 5 mmol ) of α - methylhistidine hydrochloride ( v . n . reinhold et al ., j . med . chem . 11 , 258 ( 1968 )) is dissolved in 109 ml of water and then the solution is cooled at 0 ° c . under very strong stirring , 3 . 64 ml ( 11 . 33 g , 70 . 9 mmol , 1 . 3 eq ) of bromine is added dropwise without exceeding 5 ° c . ( addition time : 2 min 30 sec ). the reaction mixture turns yellow . three minutes after the end of the addition of bromine , 20 . 22 g ( 163 . 6 mmol , 3 eq ) of l - cysteine is added and the internal temperature increases to 8 ° c . immediately , the mixture loses its color . after stirring at 0 ° c . for 1 hour , 28 . 84 ml ( 34 . 9 g , 6 eq ) of 3 - mercaptopropionic acid is added to the mixture , which is heated under strong stirring at 100 ° c . for 20 h . by continuing the protocol analogously to example 11 , 5 . 398 g ( 48 %) of α - methyl - 2 - thiohistidine in the form of a white powder is obtained . 1 h - nmr ( d 2 o , 400 mhz ): δ ( ppm )= 2 . 65 ( s , 3h ); 3 . 15 ( m , 2h ); 4 . 12 ( m , 1h ); 6 . 77 ( s , 1h ). 13 c - nmr ( d 2 o , 400 mhz ): δ ( ppm )= 24 . 8 ; 32 . 3 ; 60 . 0 ; 116 . 4 ; 123 . 2 ; 156 . 9 ; 170 . 0 .