Diisopropylethylamine → (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide

HRID 1630299Notes

Reaction equation

HRID 1630299 reaction equation
[F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]3[CH2:20][C@@H:19](O)[CH2:18][NH:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:24]1([CH2:29][C:30]([OH:32])=O)[CH:28]=[CH:27][N:26]=[N:25]1.CCN([CH:39]([CH3:41])C)C(C)C.CN(C(ON1N=N[C:52]2[CH:53]=[CH:54][CH:55]=N[C:51]1=2)=[N+](C)C)C.[F:59][P-](F)(F)(F)(F)F>CN(C=O)C>[N:24]1([CH2:29][C:30]([N:17]2[CH2:18][C@H:19]([CH2:51][C:52]3[CH:41]=[CH:39][C:55]([F:59])=[CH:54][CH:53]=3)[CH2:20][C@H:16]2[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)=[O:15])=[O:32])[CH:28]=[CH:27][N:26]=[N:25]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 190184992-(1H-1,2,3-triazol-1-yl)acetic acidHCID 56954162(2S,4R)-N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide

Product 1

HCID 45377018(2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamideYield 23%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A flask was charged with crude (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide (0.452 g), 2-(1H-1,2,3-triazol-1-yl)acetic acid (169 g, 1.33 mmol), DIEA (3.0 mL, 17 mmol), HATU (0.506 g, 1.33 mmol) and DMF (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with saturated sodium bicarbonate (aq., 10 mL). The mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue was purified by reverse phase HPLC to provide Compound 75, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.115 g, 0.222 mmol, 23% yield). 1H-NMR (400 MHz, CDCl3): δ 8.95 (s, 1H), 7.77 (d, 2H), 7.43 (d, 2H), 7.16 (dd, 2H), 7.04-6.98 (m, 4H), 6.94-6.89 (m, 3H), 5.28 (d, 1H), 5.14 (d, 1H), 4.80 (d, 1H), 4.12 (dd, 1H), 3.68 (dd, 1H), 3.26 (t, 1H), 3.02-2.92 (m, 1H), 2.89 (dd, 1H), 2.71-2.59 (m, 1H), 2.74-2.65 (m, 1H). MS (EI) for C28H25F2N5O3 found 518.2 (MH+).

Workup

  1. customquenched with saturated sodium bicarbonate (aq., 10 mL)
  2. extractionThe mixture was extracted with ethyl acetate (20 mL)
  3. washthe extract was washed with deionized water (10 mL)
  4. dry with materialbrine (10 mL), dried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customProduct was purified from the residue
  8. customwas purified by reverse phase HPLC

Sources & evidence

ORD record
ord-8e6f2d701a354f5aa8ba4c658dc36a62
Source dataset
uspto-grants-2014_07
Patent number
US08791102B2

Reaction notes

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