2,6-Lutidine → HCID 57920134, compound

HRID 19345Notes

Reaction equation

HRID 19345 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH:10]([N:14]1[CH2:18][C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][C:15]1=[O:28])[C:11]([OH:13])=O.[C:29](Cl)(=O)C(Cl)=O.Cl.[OH:36][C@@H:37]([CH2:67]O)[CH2:38][N:39]1[CH:43]=[CH:42][C:41]([NH:44]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:40]1.N1C(C)=CC=CC=1C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH:10]([N:14]1[CH2:18][C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][C:15]1=[O:28])[C:11]([NH:44][C:41]1[CH:42]=[CH:43][N:39]([CH2:38][C:37]([OH:36])([CH3:67])[CH3:29])[N:40]=1)=[O:13]

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 668948733-(2,6-Dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acidHCID 66899094HMS5552 HCl

Product 1

HCID 57920134HCID 57920134, compoundYield 36%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

In a round bottom flask under argon was placed 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (38 mg, 0.089 mmol) in dichloromethane (3 mL) and N,N-dimethylformamide (3 drops) at 25° C. To this mixture was then added a 2.0M solution of oxalyl chloride in dichloromethane (50 μL, 0.10 mmol) dropwise which resulted in gas evolution. The mixture was then stirred for 15 min at 25° C. and concentrated in vacuo. The residue was taken up in dichloromethane (3 mL) and added dropwise into a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 17 mg, 0.107 mmol), dichloromethane (3 mL) and 2,6-lutidine (50 μL, 0.18 mmol) at 25° C. The mixture was then stirred for 1 h at 25° C. and then quenched with methanol and diluted with dichloromethane. This mixture 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 (25% ethyl acetate/hexanes) afforded 3-(2,6-dichloro-phenyl)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (18 mg, 36%) as a light amber foam: HR-ES-MS m/z calculated for C26H24N4O4Cl2F2 [M+H]+ 565.1216, observed 565.1216; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.05 (s, 3H), 3.34-3.51 (m, 2H), 3.88 (s, 2H), 4.19 (d, J=18.3 Hz, 1H), 4.55 (d, J=18.3 Hz, 1H), 4.66 (s, 1H), 4.98 (s, 1H), 5.03 (dd, J=8.2, 6.0 Hz, 1H), 6.50 (d, J=2.1 Hz, 1H), 7.27 (dd, J=8.2, 7.7 Hz, 1H), 7.35 (t, J=8.7 Hz, 2H), 7.38-7.48 (m, 3H), 7.54 (d, J=2.1 Hz, 1H), 10.68 (s, 1H).

Workup

  1. customIn a round bottom flask under argon was placed
  2. customat 25° C
  3. customresulted in gas evolution
  4. concentrationconcentrated in vacuo
  5. additionadded dropwise into a flask
  6. stirringThe mixture was then stirred for 1 h at 25° C.
  7. customquenched with methanol
  8. additiondiluted with dichloromethane
  9. washThis mixture 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 (25% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-8a65ed0d509045b69afe516c5e37809e
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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