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

HRID 1630300Notes

Reaction equation

HRID 1630300 reaction equation
Cl.[F:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@H:8]2[CH2:12][NH:11][C@H:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[O:14])[CH2:9]2)=[CH:5][CH:4]=1.[N:32]1[N:33]([CH2:37][C:38](O)=[O:39])[N:34]=[CH:35][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:32]1[N:33]([CH2:37][C:38]([N:11]2[CH2:12][C@H:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:31][CH:30]=3)[CH2:9][C@H:10]2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[O:14])=[O:39])[N:34]=[CH:35][CH:36]=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 234341642-(2H-1,2,3-triazol-2-yl)acetic acidHCID 67010493(2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide hydrochloride

Product 1

HCID 45377016(2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamideYield 89.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A round bottom flask was charged with (2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide hydrochloride (150 mg, 0.37 mmole, 1 eq), prepared as in Reference 6, 2H-1,2,3-triazole-2-ylacetic acid (51 mg, 0.40 mmole, 1.1 eq), HATU (152 mg, 0.40 mmole, 1.1 eq) and DMF (1 mL). DIEA (195 μL, 1.11 mmole, 3 eq) was added and the mixture stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and deionized water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organics were washed with 5% lithium chloride (3×5 mL), 1N sodium bicarbonate (2×5 mL) and then deionized water (2×5 mL) and concentrated in vacuo. Product was purified from the residue via flash chromatography (silica, 5% MeOH, 95% EtOAc). Clean fractions were combined and concentrated in vacuo to afford Compound 50, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (171 mg, 89% yield), as a white solid. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.80 (s, 2H), 7.58-7.51 (m, 2H), 7.34-7.07 (m, 6H), 7.04-6.90 (m, 4H), 5.48 (q, 2H), 4.53-4.46 (m, 1H), 3.85-3.76 (m, 1H), 2.77-2.61 (m, 3H), 2.03-1.86 (m, 2H). MS (EI) for C28H25F2N5O3. found 517.9 (MH+).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate
  2. customThe aqueous layer was separated
  3. extractionextracted twice with ethyl acetate
  4. washThe combined organics were washed with 5% lithium chloride (3×5 mL), 1N sodium bicarbonate (2×5 mL)
  5. concentrationconcentrated in vacuo
  6. customProduct was purified from the residue via flash chromatography (silica, 5% MeOH, 95% EtOAc)
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-6ab314c0324f4baba1a4ff58d791c264
Source dataset
uspto-grants-2014_07
Patent number
US08791102B2

Reaction notes

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