WA MALI MA LTA MARIAUS 20180002309A1 DEL CHIA TANA LATIH ( 19 ) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018 /0002309 A1 Haim et al. ( 43 ) Pub . Date : Jan . 4 , 2018 (54 ) PROCESSES FOR THE PREPARATION OF A CO7D 235 / 02 (2006 . 01) DIARYLTHIOHYDANTOIN COMPOUND C07D 213 /84 ( 2006 .01 ) ( 52 ) U . S . CI. (71 ) Applicant : Aragon Pharmaceuticals , Inc. , San CPC . C07D 401 /04 ( 2013 .01 ) ; C07D 235 / 02 Diego , CA (US ) ( 2013 .01 ) ; CO7D 233 / 86 (2013 . 01 ) ; C07D 213 / 84 ( 2013 .01 ) ; B01J 31/ 24 ( 2013 .01 ) ; (72 ) Inventors : Cyril Ben Haim , Beerse (BE ) ; Andras CO7B 43/ 06 (2013 .01 ) ; BOIJ 31 / 26 (2013 .01 ) ; Horvath , Turnhout (BE ) ; Johan Erwin CO7D 213 /61 ( 2013 . 01) ??????? Edmond , Beerse (BE ) ; Jennifer Albaneze - Walker, Mol (BE ) (57 ) ABSTRACT ( 21 ) Appl . No . : 15 / 537, 859 Disclosed are processes and intermediates for the prepara tion of compound ( X ), which is currently being investigated (22 ) PCT Filed : Dec . 17, 2015 for the treatment of prostate cancer. ( 86 ) PCT No .: PCT/ US2015 / 066345 $ 371 ( C ) ( 1 ) , (X ) ( 2 ) Date : Jun . 19 , 2017 F NC N CONHMe PuuPublication Classification S ( 51 ) Int. Cl. CO7D 401/ 04 ( 2006 . 01 ) F2C CO7D 233 /86 ( 2006 .01 ) C07D 213 /61 ( 2006 .01 ) B01J 31 /24 ( 2006 .01 ) w C07B 43 / 06 ( 2006 . 01 ) B01J 31 / 26 (2006 .01 ) US 2018 /0002309 A1 Jan . 4 , 2018 PROCESSES FOR THE PREPARATION OF A [0006 ] reacting compound ( V ) with cyclobutanone in the DIARYLTHIOHYDANTOIN COMPOUND presence of sodium cyanide; in a solvent such as acetic acid , or a solvent system comprised , consisting , or consisting CROSS -REFERENCE TO RELATED essentially of an alcoholic solvent and a protic acid ; at a APPLICATIONS temperature of about 0° C . to about 20° C .; to yield the corresponding compound ( VI) ; [0001 ] This application claims priority to U . S . Provisional Patent Application No . 62 /094 ,425 , filed Dec . 19 , 2014 , which is hereby incorporated by reference in its entirety . ( 16 ) STATEMENT REGARDING FEDERALLY F SPONSORED RESEARCH OR DEVELOPMENT NC . N [0002 ] The research and development of the invention + described below was not federally sponsored . C F NH, NON FIELD OF THE INVENTION IVIV 0003 ] The present invention is directed to the preparation 210 of compound ( X ) and intermediates in its synthesis . More NC N specifically , the present invention is directed to processes for the preparation of compound ( X ), disclosed in U . S . Pat. No . 8 ,445 , 507 , issued on May 21 , 2013 , which is hereby incor F3C porated by reference in its entirety . BACKGROUND OF THE INVENTION gad [0004 ) Compound ( X ) of the present invention is currently being investigated for use in the treatment of prostate cancer. The present invention describes processes and intermediates [0007 ] reacting compound (IV ) and compound (VI ) in the for the preparation of such compound . presence of a thiocarbonylating agent; in an organic solvent ; at a temperature of about 0° C . to about 100° C .; to yield the SUMMARY OF THE INVENTION corresponding compound ( VII) ; [ 0005 ] The present invention is directed to a process for the preparation of compound ( X ) ( 1x ) - NC N F NC N CONHMe F3C F C ' N VII WidtF 0 NC NHMe Comprising , consisting of, and / or consisting essentially of F3C ( la ) F Diction F [0008 ] converting compound (VII ) to compound ( X ) , dis HON cussed in further detail below . [ 0009 ] In one embodiment, compound (VII ) is converted ?? to compound ( X ) via its corresponding carboxylic acid ( 1c ) , as shown in scheme ( 1c ), by US 2018 /0002309 A1 Jan . 4 , 2018 ( 1c ) ( le ) NCN , NC N = payoF3C sayoF3C VII VII F F NC , N , NC N CO (OC1 - talkyl ) 1 CO2H NN Fzc ?? [ 0010 ) ( i ) reacting compound (VII ) with an organomag [0014 ] ( i ) reacting compound (VII ) with an organomag nesium halide ; in the presence or absence of a lithium halide ; nesium halide ; in the presence or absence of a lithium halide ; followed by the addition of carbon dioxide gas ; in an aprotic in an aprotic organic solvent; at a temperature of about – 50° organic solvent; at a temperature of about 0° C . ; to yield the C . to about room temperature ; followed by the addition of an corresponding carboxylic acid compound ( 1c ); or, Ci- galkyl chloroformate or C - galkyl cyanoformate ; to yield [ 0011 ] ( ii ) reacting compound (VII ) under a carbon mon the corresponding ester of formula ( le ); or oxide atmosphere ; in the presence of a palladium catalyst ; in [ 0015 ] ( ii ) reacting compound (VII ) under suitable the presence of one or more phosphorus ligands ; in the alkoxycarbonylation conditions ; under a carbon mon presence of an organic base ; in a the presence of water ; in oxide atmosphere ; in the presence of a palladium an organic solvent; at a temperature of about 0° C . to about catalyst ; in the presence of one or more phosphorus ligands ; in the presence of a base ; in a C - alcoholic 100° C .; to yield the corresponding compound ( 1c ); then , solvent; at a temperature of about room temperature to about 100° C . ; to yield the corresponding compound of ( 1d ) formula ( le ) ; then F NCN . _ C02H S ( 11) F C NC N CO (OC1 - 6alkyl ) . F C FO NC . ???S NHMe Te 0 FC NC N NHMe F C [ 0012 ] reacting compound ( 1c) with a coupling agent; in an aprotic or protic solvent ; at about room temperature ; X followed by the addition of methylamine; to yield the corresponding compound ( X ) . [0016 ] treating a compound of formula ( le ) with methyl [0013 ] In another embodiment, compound ( VII ) is con amine ; in a protic or aprotic solvent; at a temperature of verted to compound ( X ) via its corresponding C1- 6alkyl ester about 0° C . to about 60° C . ; to yield the corresponding (le ), as shown in scheme ( le ), by compound ( X ) . US 2018 /0002309 A1 Jan . 4 , 2018 [0017 ] In another embodiment, compound ( VII ) is con [0027 ] The term " oxo ” or " oxido ” refers to the group verted directly to compound ( X ) , as shown in scheme (1g ), GO ) . oby en manera moderne a con [ 0028 ] Whenever the term “ alkyl ” or “ aryl” or either of their prefix roots appear in a name of a substituent ( e . g . , arylalkyl, alkylamino ) the name is to be interpreted as including those limitations given above for " alkyl ” and (1g ) “ aryl. ” Designated numbers of carbon atoms ( e . g . , C . - C . ) refer independently to the number of carbon atoms in an alkyl moiety , an aryl moiety , or in the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl and alkoxy substituents , the designated number of carbon atoms includes all of the independent members Fzc included within a given range specified . For example C1- 6 quo alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub - combinations thereof ( e . g . , C1 - 2 , C1- 3 , C1- 4 , C1- 5 , C2 - 6 , C3- 6 , C4- 6 , C5- 6 , C2 - 5 , etc . ) . VII [0029 ] In general, under standard nomenclature rules used FO throughout this disclosure , the terminal portion of the des ignated side chain is described first followed by the adjacent NCN , S functionality toward the point of attachment. Thus , for NHMe example , a “ C , - C . alkylcarbonyl” sub stituent refers to a group of the formula : F C C - C1- C6 alkyl . m [ 0018 ]. ( i ) reacting compound ( VII) in the presence of (0030 ) The term " room temperature ” or “ ambient tem molybdenum hexacarbonyl; optionally in the presence of perature ” , as used herein refers to a temperature in the range one or more reagents such as norbornadiene , tetrabutylam of from about 18° C . to about 22° C . monium bromide , or a base selected from triethylamine or [0031 ] Abbreviations used in the instant specification , DABCO ; in an organic solvent ; followed by the addition of particularly the schemes and examples, are as follows: methylamine ; at a temperature of about 60° C . to about 140° Abbreviations C . ; to yield the corresponding compound ( X ) ; or, [ 0032 ] aq aqueous [ 0019 ] ( ii ) reacting compound (VII ) under suitable amin [0033 ] BA [ 1 , 1' -biphenyl ] - 2 - amine ocarbonylation conditions ; under a carbon monoxide atmo [0034 ] Boc tert - butoxycarbonyl sphere ; in the presence of a palladium catalyst; in the [0035 ] CDI 1 , 1 ' - carbonyldiimidazole presence of one ormore phosphorus ligands; in the presence [0036 ] CPME cyclopentyl methylether of a base ; in the presence of methylamine ; in an organic [0037 ] Cy cyclohexyl solvent; at a temperature of about room temperature to about [0038 ] DABCO 1 , 4 - diazabicyclo [ 2 . 2 . 2 ] octane 100° C . ; to yield the corresponding compound ( X ) . 100391 DCM dichloromethane DETAILED DESCRIPTION OF THE [0040 ] DIEA or DIPEA diisopropylethylamine INVENTION [0041 ] DMA dimethylacetamide [ 0020 ] The term “ alkyl” whether used alone or as part of (0042 ] DMF dimethylformamide a substituent group , refers to straight and branched carbon [0043 ] DMSO methyl sulfoxide chains having 1 to 8 carbon atoms. Therefore , designated [ 0044 ] dppf 1 , 1 '- bis ( diphenylphosphino ) ferrocine numbers of carbon atoms ( e . g ., C1- 8 ) refer independently to [0045 ] h hour( s ) the number of carbon atoms in an alkylmoiety or to the alkyl 100461 HC1 hydrochloric acid portion of a larger alkyl -containing substituent. In substitu [0047 ] HPLC high performance liquid chromatography ent groups with multiple alkyl groups such as, (C1 - 6alkyl ) [0048 ] Me methyl zamino - , the C1- alkyl groups of the dialkylamino may be [0049 ] MeCN acetonitrile the same or different . [0050 ] MeOH methyl alcohol [ 0021] The term “ alkoxy” refers to an O - alkyl group , 10051] mg milligram wherein the term “ alkyl” is as defined above . [ 0052 ] MTBE methyl tert- butylether [ 0022 ] The term " cycloalkyl” refers to a saturated or 10053 ] NMP N -methyl - 2 -pyrrolidone partially saturated, monocyclic hydrocarbon ring of 3 to 8 [ 0054 ] PdCl ( dppf ) CH2Cl2 1 , 1 '- bis ( diphenylphosphino ) carbon atoms.