Diisopropylethylamine → HCID 66899236, compound

HRID 19093Notes

Reaction equation

HRID 19093 reaction equation
[F:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=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.[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH2:72])=[N:68]2)[CH2:63][O:62]1>CN(C)C=O.C(OCC)(=O)C>[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH:72][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:68]2)[CH2:63][O:62]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 66894221(S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid

Product 1

HCID 66899236HCID 66899236, compoundYield 88%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.51 g, 1.59 mmol) in N,N-dimethylformamide (6.14 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.79 mL, 4.79 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.06 g, 2.39 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.33 g, 1.67 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. over the weekend. At this time, the reaction was diluted with ethyl acetate (75 mL) and was washed with a saturated aqueous ammonium chloride solution (1×150 mL), a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.70 g, 88%) as an orange solid: HR-ES-MS m/z calculated for C26H33N4O5F [M+H]+ 501.2508, observed 501.2507; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.24 (s, 3H), 1.30 (s, 3H), 1.35-1.64 (m, 2H), 1.66-1.86 (m, 1H), 2.31 (s, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 3.96-4.14 (m, 3H), 4.20 (d, J=18.4 Hz, 1H), 4.30-4.40 (m, 1H), 4.59 (d, J=18.4 Hz, 1H), 4.83-4.93 (m, 2H), 6.43 (d, J=2.1 Hz, 1H), 7.08-7.20 (m, 1H), 7.27-7.38 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).

Workup

  1. washwas washed with a saturated aqueous ammonium chloride solution (1×150 mL)
  2. dry with materiala saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customPurification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-ac93f444cfef4708b542a723a65e8c76
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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