Patent Application: US-83765404-A

Abstract:
two methods are used to produce diaryl trisubstituted triazines . in the first method , cyanuric chloride is first reacted with a 4 - alkoxybenzylamine . the product of this reaction is then reacted with a resin - bound amine , such as 4 - alkoxybenzylamine , to ensure that the final compound will be bound to a resin . the product of this reaction is then reacted with boronic acid to produce a trisubstituted diaryl triazine . in the second method , cyanuric chloride is reacted with a benzenealkanethiol . the product of this reaction is then reacted with a resin - bound amine , such as 4 - alkoxybenzylamine , to ensure that the final compound will be bound to a resin . the product of this reaction is then reacted with m - cpba to form a sulfone , which is then reacted with a 4 - alkoxybenzylamine to form the desired trisubstituted biaryltriazine .

Description:
the present invention provides two synthetic strategies for making 1 , 3 , 5 - trisubstituted aryltriazines that can be used for generating combinatorial triazine libraries . one approach is an orthogonal approach , shown in pathway 1 in scheme 2 , and the other is sulfone chemistry , illustrated in pathway 2 in scheme 2 . using either one of these pathways , one can generate highly diversified and pure aryltriazines with versatility and ease . the present invention uses suzuki cross - coupling on a solid phase reaction to generate novel biaryl triazine libraries . cross coupling between chlorotriazine and boronic acid on pal resin was found to be a novel reaction which produced a useful triazine - based library . this reaction scheme can be used to extend diversity of already available triazine libraries , and to produce compounds which are mimics of naturally occurring biaryl alkaloid compounds . optimized conditions were found based on preliminary tests with resin bound 6 - chloro - n , n ′- bis -( 4 - methoxy - benzyl )-[ 1 , 3 , 5 ]- triazine - 2 , 4 - diamine and phenylboronic acid . it was crucial to choose an effective catalyst - ligand complex for the reaction to be performed defectively . among several catalyst - complex systems , pd ( pph 3 ) 4 ( palladium tetrakistriphenylphosphine ) proved to be the most functional and convenient catalyst , although other catalysts could also be used to catalyze this reaction . pd ( pph 3 ) 4 demonstrated greater activity than the other catalysts tested , as shown in table 1 . it can be seen from table 1 that other catalysts that can be used in the present invention include ( pd ) 2 ( dba ) 3 , ligands such as carbene and phosphine , and bases such as cs 2 o 3 , t - buok , and k 3 po 4 . under the conditions used as described hereinafter , pd 2 ( dba ) 3 with the carbene ligand had excessive activity , producing a high percentage of unknown impurities . while the phosphine ligand allowed for the reaction to proceed in comparable yields , to avoid excess material usage and extra preparation steps , commercially available pd ( pph 3 ) 4 was chosen as the preferred catalyst for the method of the present invention . for general solubility of the reagents and performance , dioxane was found to be better than toluene as the solvent . to avoid shrinking the resin , aqueous base solutions were not tested under the conditions of the present method . use of dried potassium phosphate with pd ( pph 3 ) 4 yielded high purity in preliminary experiments with phenylboronic acid . however , when tested with several other arylboronic acids , such as 3 - formylphenylboronic acid , the reaction did not proceed very well and yielded starting material and many small impurities , suggesting that cesium carbonate was a better generalized base to use in this reaction . thus , the optimized reaction condition is pd ( pph 3 ) 4 with cesium carbonate in dioxane solvent . synthesis of disubstituted monochlorotriazine was followed by the known procedure ( moon et al ., 2002 ; bork et al ., 2003 ). the suzuki cross - coupling reaction accommodated this final position by generating a disubstituted aryltriazine 2 . the catalyst was stored and dispensed within a glove box to prevent oxidation of pd ( 0 ). the reactions were heated to 90 ° c . for fifteen hours under argon gas atmosphere . anhydrous dioxane was used to ensure efficiency of the reaction . mild acidic cleavage of the resin bound molecule with 10 % trfluoroacetic acid / dichloromethane ( tfa / dcm ) gave the final trisubstituted triazine product , 3 . all of the products were analyzed for purity and identified by liquid chromatography mass spectroscopy ( lc - ms ) equipped with a diode array detector . a variety of aryl boronic acids , represented in table 2 , were tested in the suzuki reaction using optimal conditions . the sulfide substrate proved to be very valuable for library synthesis because it introduces a heterocyclic sulfone , another leaving group , which permits a final derivatization step . the present inventors previously demonstrated a generally higher purity for benzylsulfanyl triazines undergoing nucleophilic substitution than those of the 4 - methyoxybenzylamine triazines , which suggested an increased reactivity at the chloro position of the benzylsulfanyl triazine . the comparison to the suzuki cross - coupling reaction was extended by assessing a comparison of reactivity between the two substrates , amine and sulfide , as shown in scheme 2 , fig2 . to further demonstrate the efficiency and usefulness of pathway 2 , synthesis of the selected compounds in table 2 was continued in the solid phase , using oxidation with m - cpba of the benzylsulfide , followed by a replacement of benzylsulfone with 4 - methoxybenzylamine . this served as a useful comparison for both pathways , since products 3a and 3c are identical compounds . the representative arylboronic acids in table 2 were found to be effective in preparing the desired compounds via the palladium catalyzed reactions in both pathways . the purity data correlate to the three final cleaved products of scheme 1 , namely , 3a , 3b , and 3c , with either 4 - methoxybenzylamine or benzenemethanethiol as the r 2 substituent . 4 - methoxybenzylamine was used as the r 1 resin - bound amine for all reactions . ( d ) boronic acid , pd ( pph 3 ) 4 . cs 2 co 3 , dioxane , 90 ° c ., 15 hours in general , the 3b compounds exhibited higher purity than the 3a compounds , so that the final product 3c exhibited high purity . entry 7 in table 2 proved to have relatively low reactivity , primarily because of steric hindrance . in general , the results illustrate the broad tolerance of the reaction for arylboronic acids bearing a variety of substituents with both electron - withdrawing and electron - donating characteristics . in scheme 1 , r is aryl or an alkyl substituent such as phenyl , phenoxy , methoxy , ethoxy , etc . ; r1 is aryl , alkenyl , or alkyl ; and x is aryl , alkyl , alkenyl amine , alcohol , or thiol . the following are nonlimiting examples of amines that can be used in scheme 1 . structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 [ 0041 ] structure structure 33 39 34 40 35 41 36 42 37 43 38 44 the term “ aryl ” herein refers to aromatic cyclic compounds having up to 10 atoms , including carbon atoms , oxygen atoms , sulfur atoms , selenium atoms , etc . aryl groups include , but are not limited to , groups such as phenyl , substituted phenyl , naphthyl , substituted naphthyl , in which the substituent is preferably lower alkyl , halogen , or lower alkyl . “ aryl ” may also refer to fused rings systems having aromatic unsaturation . the fused ring systems can contain up to about 7 rings . an “ aryl group substituent ” as used herein includes alkyl , cycloalkyl , cycloaryl , aryl , heteroaryl , optionally substituted with 1 or more , preferably 1 to 3 , substituents selected from halo , haloalkyl , and alkyl , arylalkyl , heteroarylalkyl , alkenyl containing 1 to 2 double bonds , alkynyl containing 1 to 2 triple bonds , halo , hydroxy , polyhaloalkyl , preferably trifluoromethyl , formyl , alkylcarbonyl , arylcarbonyl , optionally substituted with 1 or more , preferably 1 to 3 , substituents selected from halo , haloalkyl , alkyl , heteroarylcarbonyl , carboxyl , alkoxycarbonyl , aryloxycarbonyl , aminocarbonyl , alkylaminocarbonyl , dialkylaminocarbonyl , arylalkylaminocarbonyl , alkoxy , aryloxy , perfluoroalkoxy , alkenyloxy , alkynyloxy , arylalkoxy , aminoalkyl , alkylaminoalkyl , dialkylaminoalkyl , arylaminoalkyl , amino , alkylamino , dialkylamino , arylamino , alkylarylamino , alkylcarbonylamino , arylcarbonylamino , amido , nitro , mercapto , alkylthio , arylthio , perfluoroalkylthio , thiocyano , isothiocyano , alkylsufinyl , alkylsulfonyl , arylsulfinyl , arylsulfonyl , aminosulfonyl , alkylaminosulfinyl , dialkylaminosulfonyl , and arylaminosulfonyl . as used herein , alkyl , alkenyl and alkynyl carbon chains , if not specified , contain from 1 to 20 carbon atoms , preferably from 1 to 16 carbon atoms , and are straight or branched . alkenyl carbon chains of from 1 to 20 carbon atoms preferably contain 1 to 8 double bonds ; the alkenyl carbon chains of 1 to 16 carbon atoms preferably contain from 1 to 5 double bonds . alkynyl carbon chains of from 1 to 20 carbon atoms preferably contain 1 to 8 triple bonds , and the alkynyl carbon chains of 1 to 16 carbon atoms preferably contain 1 to 5 triple bonds . the alkyl , alkenyl , and alkynyl groups may be optionally substituted , with one or more groups , preferably alkyl group substituents that may be the same or different . as used herein , lower alkyl , lower alkenyl , and lower alkynyl refer to carbon chains having fewer than or equal to about 6 carbon atoms . as used herein an alkyl group substituent includes halos , haloalkyl , preferably halo lower alkyl , aryl , hydroxy , alkoxy , aryloxy , alkoxy , alkylthio , arylthio , aralkyloxy , aralkylthio , carboxy , alkoxycarbonyl , oxo , and cycloalkyl . for the present invention , “ cyclic ” refers to cyclic groups preferably containing from 3 to 19 carbon atoms , preferably 3 to 10 members , more preferably 5 to 7 members . cyclic groups include hetero atoms , and may include bridged rings , fused rings , either heterocyclic , cyclic , or aryl rings . the term “ arylalkyl ” as used herein refers to an alkyl group which is substituted with one or more aryl groups . examples of arylalkyl groups include benzyl , 9 - fluorenylmethyl , naphthylmethyl , diphenylmethyl , and triphenylmethyl . “ cycloalkyl ” as used herein refers to a saturated mono - or multicyclic ring system , preferably of 3 to 10 carbon atoms , more preferably from 3 to 6 carbon atoms . cycloalkenyl and cycloalkynyl refer to mono - or multicyclic ring systems that respectively include at least one double bond and at least one triple bond . cycloalkenyl and cycloalkynyl groups may preferably contain 3 to 10 carbon atoms , with cycloalkenyl groups more preferably containing 4 to 7 carbon atoms and cycloalkynyl groups more preferably containing 8 to 10 carbon atoms . the ring systems of the cycloalkyl , cycloalkenyl and cycloalkynyl groups may be composed of one ring or two or more rings which may be joined together in a fused , bridged , or spiro - connected fashion , and may be optionally substituted with one or more alkyl group substituents . the term “ heteroaryl ” for purposes of the present application refers to a monocyclic or multicyclic ring system , preferably about 5 to about 15 members , in which at least one atom , preferably 1 to 3 atoms , is a heteroatom , that is , an element other than carbon , including nitrogen , oxygen , or sulfur atoms . the heteroaryl may be optionally substituted with one or more , preferably 1 to 3 , aryl group substituents . exemplary heteroaryl groups include , for example , furanyl , thienyl , pyridyl , pyrrolyl , n - methylpyrrolyl , quinolyinyl and isoquinolinyl . the term “ heterocyclic ” refers to a monocyclic or multicyclic ring system , preferably of 3 to 10 members , more preferably 4 to 7 members , where one or more , preferably 1 to 3 , of the atoms in the ring system is a heteroatom , i . e ., an atom that is other than carbon , such as nitrogen , oxygen , or sulfur . the heterocycle may be optionally substituted with one or more , preferably 1 to 3 , aryl group substituents . preferred substituents of the heterocyclic group include hydroxy , alkoxy , halo lower alkyl . the term heterocyclic may include heteroaryl . exemplary heterocyclics include , for example , pyrrolidinyl , piperidinyl , alkylpiperidinyl , morpholinyl , oxadiazolyl , or triazolyl . the nomenclature alkyl , alkoxy , carbonyl , etc , is used as is generally understood by those of skilled this art . as used herein , aryl refers to saturated carbon chains that contain one or more carbon atoms ; the chains may be straight or branched or include cyclic portions or may be cyclic . the term “ halogen ” or “ halide ” includes f , cl , br , and i . this can include pseudohalides , which are anions that behave substantially similarly to halides . these compounds can be used in the same manner and treated in the same manner as halides . pseudohalides include , but are not limited to , cyanide , cyanate , thiocyanate , selenocyanate , trifluoromethyl , and azide . the term “ haloalkyl ” refers to a lower alkyl radical in which one or more of the hydrogen atoms are replaced by halogen , including but not limited to , chloromethyl , trifluoromethyl , 1 - chloro - 2 - fluoroethyl , and the like . “ haloalkoxy ” refers to ro − in which r is a haloalkyl group . “ alkylene ” refers to a straight , branched , or cyclic , preferably straight or branched , bivalent aliphatic hydrocarbon group , preferably having from 1 to about 20 carbon atoms . the alkylene group is optionally substituted with one or more alkyl group substituents . there may be optionally inserted along the alkylene group one or more oxygen , sulfur , or substituted or unsubstituted nitrogen atoms , wherein the nitrogen substituent is alkyl . exemplary alkylene groups include methylene , ethylene , propylene , cyclohexylene , methylenedioxy , and ethylenedioxy . the term “ lower alkylene ” refers to alkylene groups having from 1 to 6 carbon atoms . preferred alkylene groups are lower alkylene , with alkylene of 1 to 3 atoms being particularly preferred . the term “ alkenylene ” as used herein refers to a straight , branched or cyclic , preferably straight or branched , bivalent aliphatic hydrocarbon group , preferably having from about 1 to 20 carbon atoms and at least one double bond . the alkenylene group is optionally substituted with one or more alkyl group substituents . there may be optionally inserted along the alkenylene group one or more oxygen , sulfur , or substituted or unsubstituted nitrogen atoms , where the nitrogen substituent is alkyl as previously described . as used herein , “ alkynylene ” refers to a straight , branched or cyclic bivalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms and at least one triple bond . the alkynylene group is optionally substituted with one or more alkyl group substituents . there may be optionally inserted along the alkynylene group one or more oxygen , sulfur , or substituted or unsubstituted nitrogen atoms , where the nitrogen substituent is alkyl . the term “ lower alkynylene ” refers to alkynylene groups having from 2 to 6 carbon atoms . the term “ arylene ” as used herein refers to a monocyclic or polycyclic bivalent aromatic group preferably having from 1 to 20 carbon atoms and at least one aromatic ring . the arylene group is optionally substituted with one or more alkyl group substituents . there may be optionally inserted around the arylene group one or more oxygen , sulfur , or substituted or unsubstitued nitrogen atoms , where the nitrogen substituent is alkyl . “ heteroarylene ” refers to a bivalent monocyclic or multicyclic ring system , preferably of about 5 to about 15 members , wherein one or more of the atoms in the ring system is a heteroatom . the heteroarylene may be optionally substituted with one or more aryl group substituents . as used herein , “ alkylidene ” refers to a bivalent group , such as ═ cr ′ r ″, which is attached to one atom of another group , forming a double bond . “ arylalkylidene ” refers to an alkylidene group in which either r ′ or r ″ is an aryl group . as used herein , when any particular group , such as phenyl or pyridyl , is specified , this means that the group is substituted or unsubstituted . preferred substituents , where not specified , are halo , halo lower alkyl , and lower alkyl . the term “ library ” refers to a collection of diverse compounds , in the present case , based upon a triazine scaffold . unless otherwise noted , materials and solvents were obtained from commercial suppliers and were used without further purification . anhydrous tetrahydrofuran ( thf ), 1 - methyl - 2 - pyrrolidinone ( nmp ) from acros and anhydrous 1 , 4 - dioxane from aldrich were used as reaction solvents without any prior purification . pal - aldehyde resin from midwest bio - tech was used as the solid support . for , the synthesis of building block i , general coupling reactions were performed through solution phase chemistry and were purified by flash column chromatography on merck silica gel 60 - pf 245 . all products were identified by lc - ms from agilent technology using a c18 column ( 20 × 4 . 0 mm ), with a gradient of 5 - 95 % ch 3 cn ( containing 1 % acetic acid )- h 2 o ( containing 1 % acetic acid ) as eluant . thermal reactions were performed using a standard heat block from vwr scientific products using 4 ml vials . resin filteration procedures were carried out using 70μ pe frit cartridge from applied seprations . to a suspension of 4 - formyl - 3 , 5 - dimethoxyphenoxymethyl - functionalized polystyrene resin ( pal ) ( 1 . 0 g , 1 . 1 mmol ) in thf ( 40 ml ) was added a primary amine ( 5 . 5 mmol ), followed by the addition of acoh ( 0 . 9 ml ). after shaking at room temperature for 1 hour , nahb ( oac ) 3 ( 1 . 63 g , 7 . 7 mmol ) was added , and the reaction continued shaking at room temperature for 8 hours . using a pe frit cartridge , the solvents and excess reagents were filtered out and washed with dmf , mc and meoh ( 20 ml × 3 ), ending with a final washing with mc and dried under nitrogen gas . to a solution of cyanuric chloride ( 1 . 5 g , 8 . 13 mmol ) in thf ( 50 ml ) diisopropyethylamine ( 1 . 56 ml , 8 . 94 mmol ) was added . the solution was placed in an ice - water bath ( 0 ° c .). using a syringe , 4 - methoxy - benzyl amine ( 1 . 16 ml , 8 . 94 mmol ) dissolved in thf ( 150 ml ) was slowly dripped into the reaction mixture . the reaction stirred at 0 ° c . for 3 hours . the crude compound was purified by column chromatography initially eluting with ea : hexane ( 1 : 6 ). compound was obtained as a white solid . to a solution of cyanuric chloride ( 2 g , 10 . 8 mmol ) in thf ( 50 ml ), diisopropylethylamine ( 1 . 1 eq .) was added . while cooling in an ice - water bath ( 0 ° c . ), the α - toluenethiol ( 1 . 25 g , 10 . 1 mmol ), dissolved in thf ( 150 ml ), was slowly dripped into the reaction vessel via an additional funnel . the reaction was stirred at 0 ° c . for 3 hours . the reaction mixture was evaporated in reduced pressure . the crude compound was purified by column chromatography initially eluting with dcm : hexane ( 1 : 4 ). compound was obtained as oil . resin capture of triazine scaffold via amine substitution . ( a ) to a suspension of the pal - resin - bound amine ( 125 mg , 0 . 132 mmol ) in thf ( 2 . 5 ml ) was added the 4 , 6 - dichloro -[ 1 , 3 , 5 ] triazin - 2 - yl - 4 - methoxy - benzyl - amine ( 125 mg , 0 . 91 mmol ), followed by addition of diisopropylethylamine ( 0 . 15 ml ). the reaction was placed in a heating block set at 60 ° c . for 2 . 5 hours . the solvents and excess reagent were filtered through a pe frit cartridge and washed with dmf , dcm , meoh ( 3 ml × 3 ), consecutively , ending with a final washing with dcm ( 3 ml ), and dried under nitrogen gas . ( b ) to a suspension of the pal - resin - bound amine ( 125 mg , 0 . 132 mmol ) in thf ( 2 . 5 ml ) was added the 2 - benzylsulfanyl - 4 , 6 - dichloro -[ 1 , 3 , 5 ] triazine ( 125 mg ), followed by addition of diisopropylethylamine ( 0 . 15 ml ). the reaction was placed in a heating block set at 60 ° c . for 2 . 5 hours . the solvents and excess reagent were filtered through a pe frit cartridge and washed with dmf , dcm , meoh ( 3 ml × 3 ), consecutively , ending with a final washing with dcm ( 3 ml ), and dried under nitrogen gas . to a suspension of the resin - bound scaffold ( 10 mg , 11 μmol ) in nmp ( 0 . 25 ml ) was added an amine ( 0 . 2 mmol ), followed by the addition of n - butanol ( 0 . 25 ml ) and diisopropylamine ( 30 μl , 0 . 22 mmol ). the reaction was placed in a heating block set at 120 ° c . for 3 hrs . the excess reagents were filtered through a pe frit cartridge and washed with dmf , dcm , meoh ( 1 ml × 3 ), consecutively , ending with a final washing with dcm ( 1 ml ). pd ( pph 3 ) 4 ( 7 mg , 6 . 06 mmol ) was dispensed to pre - weighed resin - bound triazine scaffold ( 10 mg , 11 μmol ) and cs 2 co 3 ( 35 mg , 0 . 1 mmol ) in a glove box . dioxane ( 1 ml ) was distributed to each reaction vial . the reaction was placed in a heating block , within a vinyl bag previously purged with argon gas , at 90 ° c . for 15 hrs the excess reagents were filtered through a pe frit cartridge and washed with sodium diethyldithiocarbamate in dmf solution ( 1 ml × 5 ), dmf ( 1 ml × 1 ), dcm , meoh ( 1 ml × 3 ), consecutively , ending with a final washing with dcm ( 1 ml ). to a solution of m - cpba ( 70 %, 270 mg , 1 . 1 mmol ) in 1 , 4 - dioxane ( 8 . 82 ml ), cooled to 0 ° c . and stirring , was added a naoh ( 1 . 09 ml , 1n ) aqueous solution . the solution of m - cpba in dioxane solution was added to the resin ( 125 mg , 0 . 13 mmol ) and gently shaken for 8 hrs at room temperature . the solution was filtered out with a pe frit cartridge and washed with 1 , 4 - dioxane ( 3 ml × 3 ) dcm , meoh ( 3 ml × 3 ), alternatively , ending with a final washing with dcm ( 3 ml ) and dried under nitrogen gas . a final substitution followed at this site . 10 % tfa in dcm was added to the resin , shaking at room temperature for 30 min . the compound was filtered from the resin , washed with dcm ( 200 μl ) and evaporated under a vacuum . the diarylsubstituted triazine libraries of the present invention can be developed as drug candidates and can be used for developing new catalysts or chemo sensors . the foregoing description of the specific embodiments will so fully reveal the general nature of the invention that other can , by applying current knowledge , readily modify and / or adapt for various application such specific embodiments without undue experimentation and without departing from the generic concept . therefore , such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments . it is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation . the means and materials for carrying out various disclosed functions may take a variety of alternative forms without departing from the invention . thus , the expressions “ means to . . . ” and “ means for . . . ” as may be found in the specification above and / or in the claims below , followed by a functional statement , are intended to define and cover whatever structural , physical , chemical , or electrical element or structures which may now or in the future exist for carrying out the recited function , whether or nor precisely equivalent to the embodiment or embodiments disclosed in the specification above . it is intended that such expressions be given their broadest interpretation . 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