Methods To help Make Improvements To VX-661enzalutamide At A Tight Budget

aetic Chemistry. Substituted 4 amino 4 benzylpiperidine intermediates were prepared from 4 cyano 4 benzylpiperidines VX-661 as previously described for 2 using a Curtius rearrangement sequence to install the 4 amino substituent. 17 A far more handy reagent combination for this transformation was discovered by treating 4 benzyl 4 carbamoylpiperidines with bis iodobenzene,36 as exemplified for the preparation of 10 . Alternatively, the reactive tert butyl sulfinimine formed from N Boc piperidin 4 one and tert butylsulfonamide was reacted in situ with VX-661 benzylic Grignard reagents to provide the 4 amino 4 benzylpiperidine scaffolds directly. 37 Hinge binding groups were introduced towards the piperidines by means of SNAr reaction of 4 chloro 7H pyrrolo pyrimidine, 6 chloro 7Hpurin 8 one, or 4 fluoro 1 1H pyrrolo pyridine,38 which occurred selectively at the far more reactive and much less hindered secondary nitrogen atom.
In addition, the piperidines enzalutamide were reacted with ethyl 4 chloro 1H pyrazolo pyridine 5 carboxylate39 followed by decarboxylation to provide the pyrazolo pyridine hinge binder. By means of these means the 4 benzyl 4 aminopiperidine analogues 2 18, 36, 37, 39, 40, 42, and 43 were prepared. To prepare the ether linked analogue 19, 1 4 piperidine 4 carboxylic acid 47 was decreased towards the alcohol 48 with lithium aluminum hydride andO benzylated to provide 49 right after doubleN deprotection . The piperidine 49 was reacted with 4 chloro 7Hpyrrolo pyrimidine to provide the test compound 19. Alternatively, formation with the major amide from 47 and reduction with borane in THF gave the 4 aminomethylpiperidine 50.
Acylation with 4 chlorobenzoyl chloride and deprotection Protein biosynthesis produced the amide 51, which was coupled towards the pyrrolopyrimidine hinge binder to provide 20. The isomeric amide 21 was prepared from enzalutamide an initial coupling of 4 chlorobenzylamine and 47 to provide the amide 52. Deprotection to 53 and introduction with the pyrrolopyrimidine VX-661 gave 21. Analogues of 21 with diverse substitution with the amide were prepared by varying the amine in the first step of this sequence. The 4 carbamido 4 aminopiperidine 53 was reacted with 4 fluoro 1 1H pyrrolo pyridine38 and 6 chloro 7H purin 8 one to provide the analogues 38 and 41, respectively. General Synthetic Chemistry. Reactions were carried out underN2. Organic solutions were dried over MgSO4 or Na2SO4. Starting materials and solvents were purchased from commercial suppliers and were applied without having further purification.
Microwave reactions were carried out using Biotage Initiator 60 or CEM microwave reactors. Flash silica chromatography was performed using Merck silica gel 60 . Ion exchange chromatography was performed using Isolute Flash SCX II or Flash NH2 resin cartridges. enzalutamide 1HNMR spectra were recorded on a Bruker AMX500 instrument at 500 MHz using internal deuterium locks. 13C NMR spectra were recorded on a Bruker AMX500 instrument at 125 MHz. Chemical shifts are reported relative to TMS and/or referenced towards the solvent in which they were measured. Combined HPLC MS analyses were recorded using a Waters Alliance 2795 separations module and Waters/Micromass LCT mass detector with electrospray ionization and with HPLC performed using Supelco DISCOVERY C18, 50 mm _ 4.
VX-661 6 mm or 30 mm _ 4. 6 mm i. d. columns, at a temperature of 22 _C with gradient elution of 10 90% MeOH/0. 1% aqueous formic acid at a flow rate of 1 mL/min as well as a run time of 3. 5 or 10 min as indicated. Compounds were detected at 254 nm using a Waters 2487 dual λ absorbance detector. All tested compounds gave 95%purity as determined by this approach. All purified synthetic intermediates gave 95% purity as determined by this approach except where indicated in the text. High resolution mass spectra were measured on an Agilent 6210 ToF HPLC MS with a Phenomenex Gemini 3 um C18 column. General Approaches for Preparation of 4 Amino 4 benzylpiperidines. 4 piperidin 4 amine . Technique A. n BuLi was added to a solution of iPr2NH in THF at 78 _C under N2.
After 10 min, a solution of tert butyl 4 cyanopiperidine 1 carboxylate in THF was added. The cloudy solution was stirred for 1 h at 78 _C. 1 4 tert butylbenzene was added along with the clear yellow brown solution was warmed enzalutamide to rt and stirred for 15 h. Water was added, along with the mixture was extracted with Et2O . The organic layers were combined, washed with brine , dried, and concentrated. Recrystallization from Et2O hexane gave tert butyl 4 4 cyanopiperidine 1 carboxylate . LC MS m/z 379 , Rt _ 2. 96 min. 1H NMR 1. 33 , 1. 47 , 1. 48 1. 52 , 2. 85 , 2. 95 3. 04 , 4. 08 4. 16 , 7. 20 7. 22 , 7. 36 7. 38 . 13C NMR 28. 4, 31. 3, 34. 5, 34. 7, 39. 2, 41. 0, 45. 4, 80. 0, 122. 0, 125. 4, 130. 0, 131. 2, 150. 5, 154. 5 ppm. A solution of tert butyl 4 4 cyanopiperidine 1 carboxylate in AcOH and conc H2SO4 was heated at 50 _C for 3 h after which at 90 _Cfor 2 h. The mixture was cooled and cautiously basified to pH 14 by the addition of 2 M NaOH aq . Boc2O in dioxane was added, along with the mixture was stirred for 24 h. The mixture was extracted with EtOAc .