Patent Application: US-49094804-A

Abstract:
the invention relates to a method of preparing nitrogen macrocycles having formula . the inventive method comprises a step involving the reaction of compounds and in order to form a compound having formula . said compound is subsequently made to react with a compound having formula in order to form a compound having formula . the latter compound is then subjected to an acid treatment

Description:
the term “ saturated or unsaturated aliphatic radical comprising from 1 to 12 carbon atoms ” denotes , in the definitions of r ′, r ″, r 1 ′ and r 1 ″ described above , in particular alkyl radicals and alkenyl radicals . among the alkyl radicals , the following are denoted more particularly for r ′, r ″, r 1 ′ and r 1 ″: the methyl , ethyl , propyl , 1 - methylethyl , butyl , 1 - methylpropyl , 2 - methylpropyl , 1 , 1 - dimethylethyl , pentyl , 1 - methyl - butyl , 2 - methylbutyl , 1 - ethylpropyl , 1 , 1 - dimethyl - propyl , 2 , 2 - dimethylpropyl or 1 , 2 - dimethylpropyl radicals . among the alkenyl radicals , the following are denoted more particularly for r ′, r ″, r 1 ′ and r 1 ″: the vinyl , 1 - propenyl , 1 - methylethenyl , 2 - propenyl , 1 - butenyl , 1 - methyl - 1 - propenyl , 2 - methyl - 1 - propenyl , 2 - butenyl , 1 - pentenyl , 1 - methyl - 1 - butenyl , 2 - methyl - 1 - butenyl , 3 - methyl - 1 - butenyl , 1 , l - dimethyl - 1 - propenyl , 2 , 2 - di - methyl - 1 - propenyl , 1 , 2 - dimethyl - 1 - propenyl , 2 - pentenyl or 2 - methyl - 2 - butenyl radicals . as illustrated by the examples described below , the process as defined above makes possible the direct synthesis of c - functionalized tetraazacycloalkanes , which are macrocycles of high added value . it is carried out in only three stages , starting from commercially available compounds . none of the three stages requires specific conditions : high dilution , inert atmosphere , long reaction times , and the like , in contrast to all the syntheses described to date . it is general and makes possible the preparation of c - functionalized cyclams and cyclens but also of 1 , 4 , 7 , 10 - tetraazatridecanes ( 2223 ). the yields are very high ( 71 - 87 % in the cyclam series ) for such compounds . the mild conditions , in particular during the final “ deprotection ” stage , make possible the introduction of highly varied organic functional groups , in contrast to the methods involving reduction , detosylation or demetallation stages . a multitude of biselectrophilic ethane or propane derivatives can thus be used , even if the examples described here are limited to commercially available compounds . after n - functionalization by suitable groups , the diversity of the functional groups introduced at a carbon atom of the ring makes it possible to adapt the method of immobilization of the macrocycle on an antibody or on a solid support according to a given application . finally , novel c - functionalized macrobicycles based on cyclam or on cyclen can be prepared according to this method . for this reason , another subject matter of the invention is the compounds of formula ( vi ) as defined above . the compounds of formula ( vi ) also make possible access to the compounds of formula ( vii ): wherein a , b , d , r and r1 are as defined above , by an appropriate treatment within the scope of a person skilled in the art . this compound of formula ( vii ) constitutes another subject matter of the present invention . according to a specific aspect , another subject matter of the present invention is the compounds of formula ( ia ): namely the two compounds of formula ( i ) as defined above for which a represents a - ch 2 - group and b represents a - ch ( r ″)- group and for which , in the definition of d , m is equal to 0 , it being understood that , in the formula ( ia ), r ″ does not represent a hydroxymethyl radical . the compounds of formula ( i ) resulting from stage ( c ) of the process of the invention ( and in particular the compounds of formula ( ia ) as defined above where r ″ does or does not denote a hydroxymethyl radical ) can be subjected to a subsequent stage ( d ) which consists in functionalizing one or more of the nitrogen atoms of their tetraazacycloalkane ring , whereby a compound is obtained which has the following formula ( i ′): the groups a , b and d have the meanings mentioned above for the compounds of formula ( i ); and each of the groups z 1 , z 2 , z 3 and z 4 ( which are identical or different ) represents , independently of the other groups : a hydrogen atom ,; or else a linear or branched alkyl radical comprising from 1 to 15 carbon atoms or a [ hetero ( aryl )] alkyl radical comprising from 7 to 12 carbon atoms ; or else a -( ch 2 ) w - y radical , in which : w represents a number greater than zero and less than or equal to 6 and more particularly less than or equal to 3 ; and y represents : a [- c (= o )] y - v radical , in which : y is equal to 0 or to 1 ; and v represents an oh radical or an or 3 radical ( in which r 3 represents an alkyl radical comprising from 1 to 6 carbon atoms and more particularly from 1 to 3 carbon atoms , optionally substituted by one or more cooh , so 3 h , po 3 h 2 or co ( nh 2 ) groups , or an nh 2 , nhr 4 or n ( r 4 ) ( r 5 ) radical ( in which r 4 and r 5 represent an alkyl radical comprising from 1 to 4 carbon atoms ); or else a - p (= o ) ( or 6 ) ( or 7 ) radical in which r 6 and r 7 each independently represent a hydrogen atom or an alkyl radical comprising from 1 to 4 carbon atoms ; or else an - so 3 h radical . the functionalization of stage ( d ) can be obtained by an appropriate treatment within the scope of a person skilled in the art . according to another aspect , another subject matter of the present invention is the process for the preparation of the compounds of formula ( i ′) comprising the additional stage ( d ) defined above . more particularly , another subject matter of the invention is the compounds capable of being obtained by subjecting the compounds of formula ( ia ) to the abovementioned functionalization stage ( d ), namely the compounds of following formula ( ia ′): wherein r ″ and z 1 , z 2 , z 3 and z 4 have the abovementioned definitions . a solution of 5 . 37 g ( 62 . 4 mmol ) of butanedione in 30 ml of acetonitrile is slowly added dropwise to a solution of 10 . 00 g ( 62 . 4 mmol ) of commercial n , n ′- bis ( 2 - aminoethyl )- 1 , 3 - propanediamine in 100 ml of acetonitrile at 0 ° c . the mixture is maintained at this temperature for two hours . after evaporating the solvent , compound 1 is isolated quantitatively in the form of a yellow solid and is used for the following stage without subsequent purification . 13 c nmr spectrometry ( 125 mhz , cdcl 3 , δ in ppm ) 10 . 7 , 18 . 3 , 23 . 3 , 39 . 2 , 42 . 0 , 45 . 6 , 46 . 6 , 49 . 0 , 51 . 1 , 68 . 1 , 73 . 3 . a solution of 4 . 95 g ( 19 . 0 mmol ) of methyl 3 - bromo - 2 -( bromomethyl ) propanoate in 20 ml of acetonitrile is slowly added dropwise to a solution of 4 . 00 g ( 19 . 0 mmol ) of compound 1 prepared in the preceding stage and of 13 . 15 g ( 95 . 0 mmol ) of potassium carbonate ( k 2 co 3 ) in 100 ml of acetonitrile at reflux . the solution is vigorously stirred and reflux is maintained for 48 hours . after filtering through celite and evaporating , compound 3 is obtained in the form of an orange - colored oil ( 5 . 58 g , yield = 95 %). 13 c nmr spectrometry ( 125 mhz , cdcl 3 , δ in ppm ) 9 . 9 , 10 . 6 , 17 . 9 , 35 . 4 , 44 . 7 , 46 . 3 , 46 . 4 , 46 . 6 , 47 . 9 , 48 . 9 , 50 . 2 , 50 . 4 , 52 . 1 , 73 . 2 , 73 . 8 , 174 . 6 . a solution of 5 . 00 g ( 16 . 2 mmol ) of compound 3 prepared in the preceding stage in 50 ml of absolute methanol is brought to reflux . 30 ml of a 35 % aqueous hydrochloric acid solution are added in small amounts . reflux is maintained for 48 hours . the mixture is cooled to 0 ° c . and the precipitate formed is filtered off and then washed with ice - cold methanol . the filtrate is evaporated and then the residue is taken up in the minimum amount of methanol . the precipitate formed is filtered off and washed with ice - cold methanol . compound 5 · 4hcl is isolated in the form of a white powder ( 4 . 55 g , yield = 76 %). overall yield starting from the tetraamine : 72 %. 1 h nmr spectrometry ( 500 mhz , d 2 o , δ in ppm ): 2 . 22 ( qt , 2h ), 3 . 10 - 3 . 80 ( m , 17h ), 3 . 78 ( s , 3h ). 13 c nmr spectrometry ( 125 mhz , d 2 o , δ in ppm ): 21 . 9 , 38 . 3 , 41 . 7 , 42 . 4 , 44 . 5 , 46 . 9 , 56 . 5 , 173 . 5 . a solution of 0 . 50 g ( 1 . 62 mmol ) of compound 3 , prepared in example a , stage ( b ), in 20 ml of absolute ethanol is brought to reflux . 3 ml of a 35 % aqueous hydrochloric acid solution are added in small amounts . reflux is maintained for 48 hours . the mixture is cooled to 0 ° c . and the precipitate formed is filtered off and washed with ice - cold ethanol . the filtrate is evaporated and then the residue is taken up in the minimum amount of ethanol . the precipitate formed is filtered off and washed with ice - cold ethanol . compound 6 · 3hcl is isolated in the form of a white powder ( 0 . 57 g , yield = 92 %). overall yield starting from the tetraamine : 87 %. 1 h nmr spectrometry ( 500 mhz , d 2 o , δ in ppm ): 1 . 55 ( qt , 2h ), 2 . 64 ( qt , 1h ), 2 . 70 - 3 . 00 ( m , 16h ). 13 c nmr spectrometry ( 125 mhz , d 2 o , δ in ppm ): 22 . 3 , 38 . 6 , 42 . 3 , 42 . 7 , 44 . 8 , 46 . 9 , 175 . 7 . elemental analysis for c 11 h 24 n 4 o 2 · 3hcl · 3h 2 o : calculated : c 32 . 40 %; h , 8 . 16 %; n , 13 . 74 % found : c 32 . 66 %; h , 8 . 03 %; n , 13 . 81 % this product is obtained according to a procedure identical to that described in example a , stage ( b ), from 8 . 00 g ( 38 . 1 mmol ) of compound 1 , 8 . 36 g ( 38 . 1 mmol ) of 1 , 3 - dibromopropan - 2 - ol and 26 . 32 g ( 190 . 5 mmol ) of k 2 co 3 . compound 4 is isolated in the form of an orange oil ( 9 . 00 g , yield = 90 %), composed of two isomers . this product is obtained according to a procedure identical to that described in example b from 1 . 15 g ( 4 . 31 mmol ) of compound 4 prepared in the preceding stage . compound 7 · 4hcl is isolated in the form of an off - white powder ( 1 . 23 g , yield = 79 %). overall yield starting from the tetraamine : 71 %. 1 h nmr spectrometry ( 200 mhz , d 2 o , δ in ppm ): 2 . 11 ( qt , 2h ), 2 . 8 - 3 . 8 ( m , 17h ). 13 c nmr spectrometry ( 50 mhz , d 2 o , δ in ppm ): 23 . 8 , 43 . 8 , 45 . 3 ( x2 ), 46 . 1 ( x2 ), 46 . 7 , 50 . 3 , 59 . 5 , 61 . 7 . this product is obtained according to a procedure identical to that described in example a , stage ( b ), from 1 . 00 g ( 4 . 73 mmol ) of compound 1 , 1 . 05 g ( 4 . 73 mmol ) of 2 , 3 - dibromopropan - l - ol and 3 . 27 g ( 23 . 65 mmol ) of k 2 co 3 . compound 8 is isolated in the form of an orange - colored oil ( 1 . 20 g , yield = 95 %) composed of several isomers . this product is obtained according to a procedure identical to that described in example d from 1 . 20 g ( 4 . 51 mmol ) of compound 8 prepared in the preceding stage . compound 9 is isolated in the form of an off - white powder ( 0 . 93 g , yield = 54 %). overall yield starting from the tetraamine : 52 %. 13 c nmr spectrometry ( 125 mhz , d 2 o , δ in ppm ): 29 . 0 , 46 . 4 , 47 . 9 , 49 . 1 , 49 . 3 , 50 . 1 , 50 . 1 , 50 . 4 , 58 . 5 , 63 . 4 . this product is obtained according to a procedure identical to that described in example a , stage ( a ), from 10 . 00 g ( 68 . 4 mmol ) of triethylenetetraamine and 5 . 88 g ( 68 . 4 mmol ) of butanedione . compound 2 is isolated quantitatively in the form of an amber solid and is used for the following stage without subsequent purification . a solution of 5 . 58 g ( 25 . 5 mmol ) of 2 , 3 - dibromopropan - 1 - ol in 20 ml of acetonitrile is slowly added dropwise to a solution of 5 . 00 g ( 25 . 5 mmol ) of compound 2 prepared in the preceding stage and of 17 . 54 g ( 127 mmol ) of k 2 co 3 in 125 ml of acetonitrile at reflux . the solution is vigorously stirred and reflux is maintained for 48 hours . after filtration through celite , evaporation and chromatography of the oil obtained on an alumina column ( eluent ch 3 oh / ch 2 cl 2 3 / 100 ), compound 10 is obtained in the form of an orange oil ( 3 . 10 g , yd = 48 %) composed of several isomers . a solution of 1 . 00 g ( 3 . 99 mmol ) of compound 10 obtained in the preceding stage in 50 ml of absolute ethanol is brought to reflux . 10 ml of a 35 % aqueous hydrochloric acid solution are added in small amounts . reflux is maintained for 48 hours . after evaporation of the solvents , the residue is taken up in the minimum amount of ice - cold ethanol . the precipitate formed is filtered off and washed with ice - cold methanol . the filtrate is evaporated and then the residue is taken up in the minimum amount of methanol . the precipitate formed is filtered off and washed with ice - cold methanol . compound 11 · 4hcl is isolated in the form of a white powder ( 0 . 80 g , yd = 57 %). 13 c nmr spectrometry ( 125 mhz , d 2 o , δ in ppm ): 42 . 1 , 43 . 3 , 43 . 9 , 44 . 0 , 44 . 5 , 44 . 9 , 46 . 9 , 56 . 0 , 59 . 5 . 9 . 04 g ( 62 . 4 mmol ) of a 40 % by weight aqueous glyoxal solution are slowly added dropwise to a solution of 10 . 00 g ( 62 . 4 mmol ) of n , n ′- bis ( 2 - aminoethyl )- 1 , 3 - pro - panediamine in 30 ml of water at 0 ° c . the mixture is maintained at this temperature for 1 hour and then stirred at ambient temperature for 10 hours . after evaporation of the water , compound 12 is isolated quantitatively in the form of a pale yellow solid and is used for the following stage without subsequent purification . 13 c nmr spectrometry ( 50 mhz , cdcl 3 , δ in ppm ) 19 . 8 , 54 . 0 - 55 . 5 ( broad ), 67 . 3 , 77 . 3 . this product is obtained according to a procedure identical to that described in example a , stage ( b ), from 1 g ( 5 . 48 mmol ) of compound 12 prepared in the preceding stage , 1 . 42 9 ( 5 . 48 mmol ) of methyl 3 - bromo - 2 -( bromomethyl ) propanoate and 3 . 80 g ( 27 . 45 mmol ) of k 2 co 3 . compound 13 is isolated in the form of an orange oil ( 1 . 46 9 , yd = 95 %) composed of two isomers . this product is obtained according to a procedure identical to that described in example f , stage ( a ), from 5 . 00 g ( 34 . 2 mmol ) of triethylenetetraamine and 4 . 95 g ( 34 . 2 mmol ) of a glyoxal solution ( 40 % in h 2 o ). compound 14 ( 4 isomers ) is isolated quantitatively in the form of a yellow oil and is used for the following stage without subsequent purification . this product is obtained according to a procedure identical to that described in example a , stage ( b ), from 3 . 00 g ( 17 . 87 mmol ) of compound 14 prepared in the preceding stage , 3 . 92 g ( 17 . 87 mmol ) of 2 , 3 - dibromo - propan - 1 - ol and 12 . 34 g ( 89 . 3 mmol ) of k 2 co 3 . compound 15 is isolated in the form of a red oil ( 3 . 95 g ). a solution of 216 . 7 g of p - tscl ( 1 . 13 mmol ) in 300 ml of pyridine is cooled to - 5 ° c . a solution of 50 g of 3 - allyloxy - 1 , 2 - propanediol ( 0 . 38 mol ) is slowly added . at the end of the addition , the mixture is maintained at ambient temperature and is stirred for 12 h . the precipitate formed is then filtered off and the filtrate is evaporated . the oil obtained is taken up in 50 ml of chloroform and is washed with 200 ml of a 0 . 5m hcl solution and then with 200 ml of a 1m na 2 co 3 solution . after evaporation of the organic phase , compound 16 is isolated in the form of a yellow oil ( 142 . 39 g , yd = 85 %). 1 h nmr ( 200 mhz , cdcl 3 ): 2 . 33 ( s , 6h ), 3 . 44 ( d , 2h ), 3 . 72 ( m , 2h ), 4 . 07 ( m , 2h ), 4 . 61 ( m , 1h ), 4 . 99 − 5 . 10 ( m , 2h ), 5 . 52 − 5 . 71 ( m , 1h ) 7 . 20 ( m , 4h ), 7 . 55 − 7 . 70 ( m , 4h ). 13 c nmr ( 50 mhz , cdcl 3 ): 21 . 7 ( x2 ), 67 . 5 , 67 . 7 , 72 . 3 , 77 . 0 , 117 . 5 , 127 . 9 ( x3 ), 129 . 9 ( x2 ), 133 . 8 ( x2 ), 145 . 3 ( x2 ). this product is obtained according to a procedure identical to that described in example a , stage ( b ), from 26 . 2 g ( 0 . 12 mol ) of compound 1 , 54 . 9 g ( 0 . 12 mol ) of compound 16 and 86 g ( 0 . 62 mol ) of k 2 co 3 . the red oil obtained is purified by chromatography on an alumina column ( eluent ch 2 cl 2 ). compound 17 is obtained in the form of a yellow oil ( 8 . 6 g , yd = 22 %) composed of two isomers . this product is obtained according to a procedure identical to that described in example b from 0 . 8 g ( 2 . 61 mmol ) of compound 17 . compound 18 · 4hcl is isolated in the form of an off - white powder . this powder is dissolved in the minimum amount of water and the solution is brought to basic ph by addition of naoh pellets . after extraction with 3 × 100 ml of chloroform and drying over mgso 4 , the solvents are evaporated . compound 18 is obtained in the form of a yellow oil ( 0 . 5 g , yd = 75 %). 1 h nmr ( 500 mhz , cdcl 3 ): 1 . 34 ( m , 2h ), 1 . 96 ( s , 4h ), 2 . 16 ( m , 1h ), 2 . 25 − 2 . 55 ( m , 14h ), 3 . 01 ( m , 1h ), 3 . 10 ( m , 1h ), 3 . 63 ( m , 2h ), 4 . 81 ( dd , 1h , j = 1 . 0 hz , 10 . 5 hz ), 4 . 91 ( dd , 1h , j = 1 . 5 hz , 15 . 5 hz ), 5 . 55 ( m , 1h , j = 5 . 5 hz , 10 . 5 hz , 15 . 5 hz ). 13 c nmr ( 125 mhz , cdc1 3 ): ( ch 2 - β ) 29 . 1 , ( ch 2 - α ) 46 . 2 , 47 . 8 , 48 . 9 , 49 . 2 , 49 . 9 , 49 . 8 , 50 . 4 , ( ch -) 56 . 8 , ( ch 2 - o ) 72 . 1 , 72 . 4 , ( ch 2 = c ) 116 . 8 , ( ch =) 134 . 8 . elemental analysis for c 13 h 28 n 4 o · h 2 o : calculated : c 56 . 89 ; h 11 . 03 ; n 20 . 42 found : c 57 . 39 ; h 10 . 98 ; n 19 . 94 a solution of 1 g ( 2 . 5 mmol ) of compound 5 · 4hcl , prepared in example a , stage ( c ), and 6 . 8 g ( 0 . 50 mol ) of k 2 co 3 in 500 ml of acetonitrile is brought to reflux . 1 . 65 g ( 9 . 9 mmol ) of ethyl 2 - bromoacetate are then added . reflux is maintained for 6 days . after filtration and evaporation of the solvent , the red oil obtained is purified by chromatography on an alumina column ( eluent ch 2 cl 2 ). compound 19 is obtained in the form of a yellow oil ( 0 . 9 g , yd = 60 %). 13 c nmr ( 125 mhz , cdcl 3 ): 14 . 8 ( x4 ), 25 . 7 , 45 . 2 , 51 . 5 ( x2 ), 52 . 1 ( x2 ), 52 . 2 , 55 . 6 ( x2 ), 55 . 7 ( x2 ), 56 . 0 ( x2 ), 56 . 7 ( x2 ), 60 . 7 ( x4 ), 172 . 2 ( x4 ), 176 . 1 . this product is obtained according to a procedure identical to that described in example i from 7 . 7 g ( 35 . 6 mmol ) of compound 9 and 21 . 66 g ( 176 . 2 mmol ) of 2 - chloro - n , n - dimethylacetamide . the red oil obtained is purified by chromatography on an alumina column ( eluent ch 2 cl 2 / meoh 98 / 2 ). compound 20 is obtained in the form of a yellow oil ( 5 . 5 g , yd = 28 %). 1 h nmr ( 500 mhz , cdc1 3 ) 1 . 56 ( m , 2h , j = 6 . 3 hz ), 2 . 39 ( m , 1h ), 2 . 45 - 3 . 10 ( m , 14h ), 2 . 85 ( s , 3h ), 2 . 87 ( s , 9h ), 2 . 93 ( s , 3h ), 2 . 97 ( s , 3h ), 3 . 01 ( s , 3h ), 3 . 02 ( s , 3h ), 3 . 15 - 3 . 6 ( m , 11h ). 13 c nmr ( 125 mhz , cdcl 3 ): ( ch 2 - β ) 24 . 2 , ( ch 3 - n ) 35 . 8 ( x3 ), 36 . 1 , 36 . 8 , 37 . 1 , 37 . 4 ( x2 ), ( ch 2 - α , ch - α ) 50 . 8 ( x2 ), 50 . 9 , 51 . 5 , 52 . 1 ( x2 ), 54 . 7 , 54 . 8 , ( ch 2 - co ) 57 . 4 ( x2 ), 58 . 0 , 60 . 2 , ( ch 2 - oh ) 62 . 5 , ( c = o ) 170 . 9 , 171 . 0 , 171 . 1 , 172 . 8 . this product is obtained according to a procedure identical to that described in example 1 from 4 . 9 g ( 19 . 1 mmol ) of compound 18 and 9 . 3 g ( 76 . 6 mmol ) of 2 - chloro - n , n - dimethylacetamide . the red oil obtained is purified by chromatography on an alumina column ( eluent ch 2 cl 2 / meoh 99 / 1 ). compound 21 is obtained in the form of a yellow oil ( 4 . 15 g , yd = 36 %). 1 h nmr ( 500 mhz , cdcl 3 ): 1 . 40 ( m , 2h ), 2 . 3 - 3 . 5 ( m , 49h ), 3 . 72 ( m , 2h ), 4 . 93 ( d , 1h , j = 10 . 3 hz ), 5 . 05 ( dd , 1h , j = 1 . 8 hz , 17 hz ), 5 . 60 ( m , 1h ). 13 c nmr ( 125 mhz , cdcl 3 ) ( ch 2 - β ) 23 . 4 , ( ch 3 - n ) 35 . 6 ( x2 ), 35 . 7 , 35 . 9 , 37 . 1 , 37 . 2 , 37 . 3 , 37 . 5 , ( ch 2 - 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