2,6-Lutidine → HCID 178459287, compound

HRID 19306Notes

Reaction equation

HRID 19306 reaction equation
[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C@H:15]2[CH2:18][C@@H:17]([CH3:19])[CH2:16]2)[C:11]([OH:13])=O)[C:7](=[O:20])[CH:6]=1.[C:25](Cl)(=O)C(Cl)=O.Cl.[OH:32][C@@H:33]([CH2:63]O)[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:36]1.N1C(C)=CC=CC=1C>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C@H:15]2[CH2:16][C@@H:17]([CH3:19])[CH2:18]2)[C:11]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C:33]([OH:32])([CH3:63])[CH3:25])[N:36]=2)=[O:13])[C:7](=[O:20])[CH:6]=1

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 66899094HMS5552 HClHCID 178461460HCID 178461460, compound

Product 1

HCID 178459287HCID 178459287, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(cis-3-methyl-cyclobutyl)-propionic acid (92 mg, 0.26 mmol), dichloromethane (6 mL) and N,N-dimethylformamide (3 drops) at 25° C. To this mixture was added a 2.0M solution of oxalyl chloride in dichloromethane (300 μL, 0.60 mmol) dropwise, which resulted in gas evolution. The mixture was stirred for 15 min at 25° C. and then concentrated in vacuo. The residue was taken up in dichloromethane (5 mL) and added dropwise into another flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 50 mg, 0.31 mmol), dichloromethane (5 mL) and 2,6-lutidine (150 μL, 0.52 mmol) at 25° C. and stirred for 1 h at 25° C. The mixture was quenched with methanol and then diluted with dichloromethane. The organic layer was then washed with a 1N aqueous hydrochloric acid solution, dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 33% ethyl acetate/hexanes) and then reverse phase HPLC afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(cis-3-methyl-cyclobutyl)-propionamide, as a mixture of enantiomers (17 mg, 13%): HR-ES-MS m/z calculated for C25H31N4O4Cl [M+H]+ 487.2107, observed 487.2105; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.2 Hz, 3H), 1.05 (s, 3H), 1.06 (s, 3H), 1.16-1.29 (m, 2H), 1.29-1.40 (m, 1H), 1.74-2.25 (m, 6H), 3.90 (s, 2H), 4.21 (d, J=18.3 Hz, 1H), 4.57 (d, J=18.3 Hz, 1H), 4.71 (dd, J=9.6, 5.8 Hz, 1H), 4.78 (s, 1H), 6.44 (d, J=2.2 Hz, 1H), 7.37 (td, J=7.9, 1.7 Hz, 1H), 7.47 (td, J=7.9, 1.4 Hz, 1H), 7.50-7.53 (m, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.66 (dd, J=7.9, 1.4 Hz, 1H), 10.75 (s, 1H).

Workup

  1. customIn a round bottom flask under argon was placed
  2. customat 25° C
  3. customwhich resulted in gas evolution
  4. concentrationconcentrated in vacuo
  5. additionadded dropwise into another flask
  6. stirringstirred for 1 h at 25° C
  7. customThe mixture was quenched with methanol
  8. additiondiluted with dichloromethane
  9. washThe organic layer was then washed with a 1N aqueous hydrochloric acid solution
  10. dry with materialdried over sodium sulfate
  11. concentrationconcentrated in vacuo with silica gel (2 g)
  12. customPurification by Biotage flash chromatography (40S column, 33% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-1b9f60744e094db58887bbc5a234e35a
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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