Dimethylformamide → biphenyl-2-yl((2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanone

HRID 60784

Reaction equation

HRID 60784 reaction equation
[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([OH:9])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.CN([C:19]([O:23]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN([CH2:45][CH3:46])CC.[OH-:47].[Na+].C[N:50]([CH:52]=O)[CH3:51]>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:50]1[CH2:52][C@H:45]([OH:47])[CH2:46][C@H:51]1[CH2:19][OH:23])=[O:9]

Participants

6

Reactant 5

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 70357o-Phenylbenzoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)

Product 1

HCID 89739118biphenyl-2-yl((2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanoneYield 45%

Conditions

Temperature
0 °C

Procedure

Formation of the amide bond was carried out using an adaptation of General Method A, above. A mixture of commercially available (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.26 g, 15 mmol) in 50 mL of DCM/TFA (3:2, v/v) was stirred at rt for 4 h, concentrated in vacuo to give a brown oil as a crude TFA salt of (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol, which was dissolved in DMF (28 mL), added with biphenyl-2-carboxylic acid (3.05 g, 15.4 mmol) and HATU (5.86 g, 15.4 mmol). The resulting solution was cooled to 0° C., added with Et3N (8.8 mL, 63 mmol) dropwise and was allowed to warm to rt gradually and stirred overnight. 2M NaOH (aq.) was added and the mixture was extracted with EtOAc (3×). The combined EtOAc solution was washed with brine, dried over MgSO4 and concentrated in vacuo to a brown oil, which was purified by column chromatography on silica gel (10% MeOH in EtOAc) to provide biphenyl-2-yl((2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl)methanone as an off-white solid (2.0 g, 45% yield over two steps). 1H NMR (CDCl3, 400 MHz) δ 7.59-7.57 (m, 2H), 7.54-7.40 (m, 7H), 4.44 (brs, 1H), 4.10 (s, 1H), 3.77-3.72 (m, 1H), 3.62 (brs, 1H), 3.32 (brs, 1H), 3.04-2.96 (m, 1H), 2.60 (brs, 1H), 2.00-1.95 (m, 1H), 1.61 (brs, 2H). MS (ESI) 298.04 (M+H).

Workup

  1. temperatureto warm to rt gradually
  2. extractionthe mixture was extracted with EtOAc (3×)
  3. washThe combined EtOAc solution was washed with brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo to a brown oil, which
  6. customwas purified by column chromatography on silica gel (10% MeOH in EtOAc)

Sources & evidence

ORD record
ord-c299a602a6dc4d21b10db5523cdf6f0e
Source dataset
uspto-grants-2016_09
Patent number
US09440982B2

Linked notes

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