Diisopropylethylamine → (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide

HRID 2365727Notes

Reaction equation

HRID 2365727 reaction equation
[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]([CH3:32])([CH3:31])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C:23]([O:22][CH3:21])([CH3:31])[CH3:32])[N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 668999341-(2-methoxy-2-methylpropyl)-1H-pyrazol-3-amineHCID 70945105(S)-3-Cyclopentyl-2-(1-oxoisoindolin-2-yl)propanoic acid

Product 1

HCID 70674567(S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideYield 56.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 9, 0.1 g, 0.37 mmol) and 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 94, 0.065 g, 0.38 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (0.19 g, 0.44 mmol) in methylene chloride (10 mL) was added N,N-diisopropylethylamine (0.19 mL, 1.10 mmol) and the resulting solution stirred at room temperature for 19 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium chloride solution, and dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF15-40 g column, 50%-70% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (0.063 g, 0.21 mmol, 41%) as an off white solid; [α]29D=−47.5° (c=0.28, chloroform); HR-ES(+) m/e calcd for C24H32N4O3 [M+Na]+ 447.2366, observed 447.2368; 1H NMR (300 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.62 (m, 2H), 7.48 (d, J=2.3 Hz, 1H), 7.45-7.54 (m, 1H), 6.43 (d, J=2.3 Hz, 1H), 5.05 (dd, J=10.7, 5.0 Hz, 1H), 4.87 (d, J=17.8 Hz, 1H), 4.53 (d, J=17.8 Hz, 1H), 3.99 (s, 2H), 3.15 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H), 0.98-2.10 (m, 11H).

Workup

  1. washwashed with a 1 N hydrochloric acid solution (15 mL)
  2. dry with materiala saturated sodium chloride solution, and dried over magnesium sulfate
  3. filtrationThe mixture was filtered
  4. customevaporated
  5. customthe resulting material purified

Sources & evidence

ORD record
ord-19604fea9f774e19964022de9e75145d
Source dataset
uspto-grants-2014_04
Patent number
US08697705B2

Reaction notes

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