Carbodiimide → 3-Hydroxy-4-methoxy-pyridine-2-carboxylic acid (2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-amide

HRID 403362

Reaction equation

HRID 403362 reaction equation
[OH:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.C(#N)C.N=C=N.ON1C2N=CC=CC=2N=N1.[NH2:36][C:37]1[N:38]=[C:39]([CH:42]2[CH2:47][CH2:46][N:45]([C:48](=[O:60])[CH2:49][N:50]3[C:54]([CH3:55])=[CH:53][C:52]([C:56]([F:59])([F:58])[F:57])=[N:51]3)[CH2:44][CH2:43]2)[S:40][CH:41]=1>C(OCC)(=O)C>[CH3:55][C:54]1[N:50]([CH2:49][C:48]([N:45]2[CH2:44][CH2:43][CH:42]([C:39]3[S:40][CH:41]=[C:37]([NH:36][C:10]([C:3]4[C:2]([OH:1])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][N:4]=4)=[O:12])[N:38]=3)[CH2:47][CH2:46]2)=[O:60])[N:51]=[C:52]([C:56]([F:59])([F:57])[F:58])[CH:53]=1

Participants

7

Reactant 5

HCID 160435CarbodiimideHCID 181649HOAtHCID 110411213-Hydroxy-4-methoxypyridine-2-carboxylic acidHCID 21895542Acetonitrile triethylamineHCID 669564011-[4-(4-Amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Product 1

HCID 867041643-Hydroxy-4-methoxy-pyridine-2-carboxylic acid (2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-amide

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 3-hydroxy-4-methoxy-pyridine-2-carboxylic acid acid (70 mg, 0.34 mmol) in 4 ml of acetonitrile triethylamine (0.13 mL, 0.96 mmol), 1-ethyl-3-dimethylaminopropyl)carbodiimide (77 mg, 0.41 mmol) and 1-hydroxy-7-azabenzotriazole (53 mg, 0.38 mmol) were added at RT. After stirring 15 min at RT, 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (120 mg, 0.32 mmol) was added to the reaction mixture. After stirring 16 h at RT, the reaction mixture was diluted with 20 ml of ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 1 M hydrochloric acid and brine, dried over sodium sulfate and evaporated under reduced pressure. The remainder was purified by column chromatography on silica gel (ethylacetate/cyclohexane 1:1 to 8:2) to give 3-hydroxy-4-methoxy-pyridine-2-carboxylic acid (2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-amide (Compound No. 1.g.025) as a beige solid. 1H-NMR (400 MHz, CDCl3): δ=1.64-1.77 (m, 2H), 2.05-2.16 (m, 2H), 2.27 (s, 3H), 2.81-2.89 (m, 1H), 3.12-3.28 (m, 2H), 3.92 (s, 3H), 3.94-3.99 (m, 1H), 4.44-4.51 (m, 1H), 4.93 (d, 2H), 6.27 (s, 1H), 6.89 (d, 1H), 7.59 (s, 1H), 8.00 (d, 1H). MS: m/z=525 (M+1).

Workup

  1. stirringAfter stirring 16 h at RT
  2. washThe organic layer was washed with saturated aqueous sodium bicarbonate solution, 1 M hydrochloric acid and brine
  3. dry with materialdried over sodium sulfate
  4. customevaporated under reduced pressure
  5. customThe remainder was purified by column chromatography on silica gel (ethylacetate/cyclohexane 1:1 to 8:2)

Sources & evidence

ORD record
ord-80ce9b927b2e48eea76a47c084857335
Source dataset
uspto-grants-2014_06
Patent number
US08748431B2

Linked notes

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