2,6-Lutidine → HCID 178459288, compound

HRID 19303Notes

Reaction equation

HRID 19303 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 178461461HCID 178461461, compound

Product 1

HCID 178459288HCID 178459288, compoundYield 36%

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-(trans-3-methyl-cyclobutyl)-propionic acid (100 mg, 0.29 mmol), dichloromethane (5 mL) and N,N-dimethylformamide (3 drops) at 25° C. To this mixture was added a 2.0M solution of oxalyl chloride in dichloromethane (180 μL, 0.36 mmol) dropwise, which resulted in gas evolution. The mixture was stirred for 15 min at 25° C. and then concentrated in vacuo. This 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, 55 mg, 0.35 mmol), dichloromethane (5 mL) and 2,6-lutidine (180 μL, 0.58 mmol) at 25° C. and stirred for 1.5 h at 25° C. and then quenched with methanol. The mixture was diluted with dichloromethane and washed with a 1N aqueous hydrochloric acid solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo with silica gel (2 g). Purification by Biotage flash chromatography (40S column, 25% ethyl acetate/hexanes) 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-(trans-3-methyl-cyclobutyl)-propionamide (51 mg, 36%) as a light amber foam: HR-ES-MS m/z calculated for C25H31N4O4Cl [M+H]+ 487.2107, observed 487.2107; 1H NMR (500 MHz, DMSO-d6) δ ppm 1.06 (d, J=6.8 Hz, 9H), 1.48-1.57 (m, 1H), 1.65-1.73 (m, 1H), 1.75-1.83 (m, 1H), 1.88-2.01 (m, 3H), 2.14-2.26 (m, 1H), 2.28-2.37 (m, 1H), 3.90 (s, 2H), 4.20 (d, J=18.6 Hz, 1H), 4.58 (d, J=18.6 Hz, 1H), 4.66 (s, 1H), 4.73 (dd, J=9.3, 6.3 Hz, 1H), 4.78 (s, 1H), 6.44 (d, J=2.4 Hz, 1H), 7.37 (td, J=7.8, 1.5 Hz, 1H), 7.47 (td, J=7.8, 1.5 Hz, 1H), 7.51 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.65 (dd, J=7.8, 1.5 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 1.5 h at 25° C.
  7. customquenched with methanol
  8. additionThe mixture was diluted with dichloromethane
  9. washwashed with a 1N aqueous hydrochloric acid solution
  10. customThe organic layer was separated
  11. dry with materialdried over sodium sulfate
  12. concentrationconcentrated in vacuo with silica gel (2 g)
  13. customPurification by Biotage flash chromatography (40S column, 25% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-df225d38c7414c8f965d1d6c839ad208
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

Loading…