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

HRID 2365725Notes

Reaction equation

HRID 2365725 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.[NH2:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][OH:30])[N:23]=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:21][C:22]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][OH:30])[N:23]=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 509897073-(3-amino-1H-pyrazol-1-yl)propan-1-olHCID 70945105(S)-3-Cyclopentyl-2-(1-oxoisoindolin-2-yl)propanoic acid

Product 1

HCID 70674451(S)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamideYield 24.4%

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, 80 mg, 0.29 mmol) and 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared as in US 20080021032, Example 23, 49 mg, 0.35 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.15 g, 0.35 mmol) in methylene chloride (8 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) dropwise and the resulting solution stirred at room temperature for 4 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (25 mL), a saturated sodium bicarbonate solution (25 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-12 g column, 50-70% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (28 mg, 24%) as an off white solid: HR-ES(+) m/e calcd for C22H28N4O3 [M+H]+ 397.2234, observed 397.2233; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94-2.34 (m, 7H), 4.04 (t, J=6.79 Hz, 3H), 4.37-5.28 (m, 6H), 6.39 (s, 2H), 7.31-7.90 (m, 8H), 10.86 (s, 2H).

Workup

  1. washwashed with a 1 N hydrochloric acid solution (25 mL)
  2. dry with materiala saturated sodium bicarbonate solution (25 mL) dried over magnesium sulfate
  3. filtrationThe mixture was filtered
  4. customevaporated
  5. customthe resulting material purified

Sources & evidence

ORD record
ord-98bcaa4f99e14f6da99400c79e36959d
Source dataset
uspto-grants-2014_04
Patent number
US08697705B2

Reaction notes

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