Hydrochloric Acid → N-(2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine

To a mixture of water (850 ml) and concentrated hydrochloric acid (240 ml) is added a solution of 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl ester (304.5 g, 0.72 mol) in THF (600 ml) dropwise at 65° C. The addition and reaction are complete in 40 minutes. THF is then stripped under vacuum; residual aqueous layer is extracted with 2 L MTBE (to remove remaining (2,4-dichloro-thiazol-5-yl)-methanol). Neutralized by addition of NaOH (30%, 200 ml) and extracted twice with MTBE (1.5 L). Combined organic layers are washed with brine (3 L) then clarified (to remove insoluble). The organic layer is then concentrated under vacuum to afford 220 g of N-(2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine as a pink powder. Yield 95% (HPLC=99% area). Mass spectrum (ion spray): m/z=322 (M+1); 1H NMR (400 MHz, CDCl3): δ=3.73 (2H, s), 3.17 (2H, m), 2.56 (3H, m). 2.31 (2H, d), 2.17 (1H, s, NH), 1.76 (2H, m), 1.68 (1H, m), 1.46 (2H, m), 0.92 (6H, d); 13C NMR (100 MHz, CDCl3): δ=20.6, 27.09, 28.88, 46.39, 47.20, 58.10, 58.52, 131.88, 137.30, 150.13.

1. additionThe addition and reaction
2. extractionresidual aqueous layer is extracted with 2 L MTBE (to remove remaining (2,4-dichloro-thiazol-5-yl)-methanol)
3. additionNeutralized by addition of NaOH (30%, 200 ml)
4. extractionextracted twice with MTBE (1.5 L)
5. washCombined organic layers are washed with brine (3 L)
6. custom(to remove insoluble)
7. concentrationThe organic layer is then concentrated under vacuum

ORD-Eintrag

ord-11390c994ddc4a4ab23852d175c44c2d

Quelldatensatz

uspto-grants-2009_04

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07521462B2