Acetic Acid → 4-{[(2,4-Dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl ester

HRID 2111898Notes

Reaction equation

HRID 2111898 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[S:21][C:22]([CH:26]=O)=[C:23]([Cl:25])[N:24]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:26][C:22]2[S:21][C:20]([Cl:19])=[N:24][C:23]=2[Cl:25])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 176Acetic AcidHCID 14886722,4-Dichloro-1,3-thiazole-5-carboxaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 15380699tert-Butyl 4-(isobutylamino)piperidine-1-carboxylate

Product 1

HCID 685764924-{[(2,4-Dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl esterYield 31.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-(isobutylamino)-piperidine-1-carboxylic acid tert-butyl ester (797 mg, 2.28 mmol, 1 eq.) and 2,4-dichloro-5-thiazolecarboxaldehyde (500 mg, 2.75 mmol, 1.2 eq) in anhydrous dimethylformamide (10 ml), is added glacial acetic acid (130 uL, 2.28 mmol, 1 eq.) and NaBH(OAc)3 (677 mg, 3.19 mmol, 1.4 eq.). The reaction mixture is stirred at room temperature for 3 days and then water and ethyl acetate are added. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organics are washed with water, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue is purified on silica gel with 0 to 25% THF in hexanes to give 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl ester (303 mg, 31%): m/z=422 (M+1); 1H NMR (250 MHz, CDCl3): δ=4.35 (2H, brd), 3.87 (2H, s), 2.80 (3H, m), 2.42 (2H,d), 1.86 (3H, m), 1.61 (11H, m), 1.06 (6H, d).

Workup

  1. customThe layers are separated
  2. extractionthe aqueous layer is extracted with ethyl acetate
  3. washThe combined organics are washed with water
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue is purified on silica gel with 0 to 25% THF in hexanes

Sources & evidence

ORD record
ord-ef5604f391264041b22e798313ca9b66
Source dataset
uspto-grants-2009_04
Patent number
US07521462B2

Reaction notes

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