Tris(hydroxymethyl)aminomethane → 1,1-dimethylethyl (2R,6S)-4-{[4-(2-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-1-methyl-2-oxoethyl)phenyl]methyl}-2,6-dimethyl-1-piperazinecarboxylate

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Reaction Steps

A mixture of D46 (100 mg, 0.27 mmol), polymer-supported DCC (310 mg, 1.3 mmol/g, 0.40 mmol) and 1-hydroxybenzotriazole (50 mg, 0.324 mmol) in 2:1 DMF/DCM (3 ml) was treated with D2 (51 mg, 0.26 mmol) and the mixture stirred overnight. Scavenger resins (PS-trisamine, PS-isocyanate and Si-carbonate) together with DCM (˜3 ml) were added. The mixture was stirred for ˜3 h and then filtered and concentrated to give 1,1-dimethylethyl (2R,6S)-4-{[4-(2-{4-[(4-fluorophenyl)amino]-1-piperidinyl}-1-methyl-2-oxoethyl)phenyl]methyl}-2,6-dimethyl-1-piperazinecarboxylate. MS (ES): MH+ 553. This whole was dissolved in DCM (2 ml) and TFA (1 ml) then stirred for 1.5 h. The solvents were removed in vacuo and the residue re-evaporated from toluene and ether. Purification using an Isolute SCX cartridge eluting with MeOH followed by 2M NH3 in MeOH gave the title compound. MS (ES): MH+ 453. This whole was dissolved in DCM and treated with 1.1 eq 1M HCl in ether to give a hydrochloride salt of the title compound (122 mg). MS (ES): MH+ 453.

Provenance & Evidence