Different Ways To Improve VX-661enzalutamide At A Tight Budget

aetic Chemistry. Substituted 4 amino 4 benzylpiperidine intermediates had been prepared from 4 cyano 4 benzylpiperidines VX-661 as previously described for 2 utilizing a Curtius rearrangement sequence to install the 4 amino substituent. 17 A additional practical reagent combination for this transformation was identified 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 a single 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 had been introduced towards the piperidines by means of SNAr reaction of 4 chloro 7H pyrrolo pyrimidine, 6 chloro 7Hpurin 8 a single, or 4 fluoro 1 1H pyrrolo pyridine,38 which occurred selectively at the additional reactive and less hindered secondary nitrogen atom.
In addition, the piperidines enzalutamide had been reacted with ethyl 4 chloro 1H pyrazolo pyridine 5 carboxylate39 followed by decarboxylation to provide the pyrazolo pyridine hinge binder. Through these signifies the 4 benzyl 4 aminopiperidine analogues 2 18, 36, 37, 39, 40, 42, and 43 had been 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 soon 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 various substitution with the amide had been prepared by varying the amine within the very 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 a single to provide the analogues 38 and 41, respectively. Common Synthetic Chemistry. Reactions had been carried out underN2. Organic solutions had been dried over MgSO4 or Na2SO4. Starting materials and solvents had been purchased from commercial suppliers and had been applied devoid of further purification.
Microwave reactions had been carried out utilizing Biotage Initiator 60 or CEM microwave reactors. Flash silica chromatography was performed utilizing Merck silica gel 60 . Ion exchange chromatography was performed utilizing Isolute Flash SCX II or Flash NH2 resin cartridges. enzalutamide 1HNMR spectra had been recorded on a Bruker AMX500 instrument at 500 MHz utilizing internal deuterium locks. 13C NMR spectra had been 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 had been measured. Combined HPLC MS analyses had been recorded utilizing a Waters Alliance 2795 separations module and Waters/Micromass LCT mass detector with electrospray ionization and with HPLC performed utilizing 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 had been detected at 254 nm utilizing 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 within the text. High resolution mass spectra had been measured on an Agilent 6210 ToF HPLC MS with a Phenomenex Gemini 3 um C18 column. Common Techniques for Preparation of 4 Amino 4 benzylpiperidines. 4 piperidin 4 amine . Approach A. n BuLi was added to a answer of iPr2NH in THF at 78 _C below N2.
After 10 min, a answer of tert butyl 4 cyanopiperidine 1 carboxylate in THF was added. The cloudy answer was stirred for 1 h at 78 _C. 1 4 tert butylbenzene was added and the clear yellow brown answer was warmed enzalutamide to rt and stirred for 15 h. Water was added, and the mixture was extracted with Et2O . The organic layers had been 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 answer of tert butyl 4 4 cyanopiperidine 1 carboxylate in AcOH and conc H2SO4 was heated at 50 _C for 3 h and after that 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, and the mixture was stirred for 24 h. The mixture was extracted with EtOAc .