Diisopropylethylamine → ethyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylate

HRID 1042049Notes

Reaction equation

HRID 1042049 reaction equation
[CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH2:47]([O:49][C:50]([C:52]1[N:53]=[C:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[S:55][CH:56]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[N:53]=[C:54]([CH:57]2[CH2:62][CH2:61][N:60]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:59][CH2:58]2)[S:55][CH:56]=1)=[O:51])[CH3:48]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 5961182-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acidHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 66956430Ethyl 2-(4-piperidinyl)-4-thiazolecarboxylate monohydrochloride

Product 1

HCID 66911511ethyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylateYield 88%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (9.1 g, 36.1 mmol) in DMF (100 mL) is added diisopropylethylamine (45 mL, 216 mmol), followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (15.5 g, 39.7 mmol). After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester hydrochloride (10 g, 36.1 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (300 mL), washed with saturated aqueous sodium bicarbonate solution (300 mL), 1M HCl solution (300 mL), and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10:1) to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (13.6 g, 88%). 1H-NMR (400 MHz, CDCl3): δ=1.40 (t, 3H), 1.70-1.85 (m, 2H), 2.16-2.30 (m, 2H), 2.32 (s, 3H), 2.79-2.89 (m, 1H), 3.22-3.43 (m, 1H), 4.03-4.12 (m, 1H), 4.42 (q, 3H), 4.54-4.69 (m, 1H), 4.93-5.08 (2d, 2H (diastereotopic)), 6.35 (s, 1H), 8.10 (br, 1H). MS: m/z=209 (M+1).

Workup

  1. stirringAfter stirring overnight at RT
  2. customsolvent is evaporated
  3. dissolutionthe resulting yellow oil is dissolved in ethylacetate (300 mL)
  4. washwashed with saturated aqueous sodium bicarbonate solution (300 mL), 1M HCl solution (300 mL), and brine (100 mL)
  5. dry with materialThe organic layer is dried over sodium sulfate
  6. filtrationfiltered
  7. customevaporated under reduced pressure
  8. customThe crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10:1)

Sources & evidence

ORD record
ord-cb83cf1bc3b14f59bd3e34a3f0490539
Source dataset
uspto-grants-2013_10
Patent number
US08557821B2

Reaction notes

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