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

HRID 2111916Notes

Reaction equation

HRID 2111916 reaction equation
O.Cl.C(OC([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:21][C:22]2[S:26][C:25]([Cl:27])=[N:24][C:23]=2[Cl:28])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:11]1)=O)(C)(C)C>C1COCC1>[CH3:19][CH:18]([CH3:20])[CH2:17][N:16]([CH2:21][C:22]1[S:26][C:25]([Cl:27])=[N:24][C:23]=1[Cl:28])[CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 962WaterHCID 685764924-{[(2,4-Dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl ester

Product 1

HCID 57640332N-(2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amineYield 95%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-11390c994ddc4a4ab23852d175c44c2d
Source dataset
uspto-grants-2009_04
Patent number
US07521462B2

Reaction notes

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