Diisopropylethylamine → 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4,4-trifluoro-butyramide

HRID 19341Notes

Reaction equation

HRID 19341 reaction equation
[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:11](O)=[O:12])[C:7](=[O:19])[CH:6]=1.[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]2)[CH2:27][O:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C:15]([F:17])([F:18])[F:16])[C:11]([NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:28]3[CH2:27][O:26][C:25]([CH3:37])([CH3:24])[O:29]3)[N:32]=2)=[O:12])[C:7](=[O:19])[CH:6]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 59344941(R)-1-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-3-amineHCID 668951842-[4-(2-Chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4,4-trifluoro-butyric acid

Product 1

HCID 866352422-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4,4-trifluoro-butyramideYield 77.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4,4-trifluoro-butyric acid (144 mg, 0.41 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 97 mg, 0.49 mmol) in N,N-dimethylformamide (4 mL). To this mixture was added N,N-diisopropyethylamine (200 μL, 1.23 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (271 mg, 0.62 mmol) and stirred for 16 h at 25° C. After this time, the mixture was diluted with ethyl acetate (25 mL) and washed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), dried over sodium sulfate, and then concentrated with silica gel (2 g). Purification by Biotage flash chromatography (Aspire 40 g column, 80% ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4,4-trifluoro-butyramide (168 mg, 77%) as a white foam: HR-ES-MS m/z calculated for C23H24N4O5ClF3 [M+H]+ 529.1460, observed 529.1457.

Workup

  1. customIn a round bottom flask under argon was placed
  2. washwashed with a saturated aqueous solution of ammonium chloride (25 mL), saturated aqueous solution of sodium bicarbonate (25 mL)
  3. dry with materiala saturated aqueous solution of sodium chloride (25 mL), dried over sodium sulfate
  4. concentrationconcentrated with silica gel (2 g)
  5. customPurification by Biotage flash chromatography (Aspire 40 g column, 80% ethyl acetate)

Sources & evidence

ORD record
ord-5f57901b33654b9f876761f5c6473a23
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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