2,6-Lutidine → 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(3-oxo-cyclobutyl)-propionamide

HRID 546181Notes

Reaction equation

HRID 546181 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30]([CH3:39])([CH3:38])[CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:13]([NH:37][C:34]2[CH:35]=[CH:36][N:32]([CH2:31][C:30]([O:29][CH3:28])([CH3:38])[CH3:39])[N:33]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 668999341-(2-methoxy-2-methylpropyl)-1H-pyrazol-3-amineHCID 67191351HCID 67191351, compound

Product 1

HCID 671884682(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(3-oxo-cyclobutyl)-propionamideYield 52%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent4×

Conditions

Temperature
25 °C

Procedure

A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionic acid (65 mg, 0.20 mmol) in methylene chloride (8 mL) was cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 120 μL, 0.24 mmol) and N,N-dimethylfomamide (one drop) which was then stirred at 0° C. for 20 minutes and 40 min at 25° C. After this time, the reaction was concentrated in vacuo and azeotroped with methylene chloride (10 ml). In a separate flask a solution of 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (36 mg, 0.22 mmol), 2,6-lutidine (34 μL, 0.29 mmol) in methylene chloride (8 mL) was cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride in methylene chloride (5 mL) dropwise. After addition was complete the reaction was then stirred at 0° C. for 15 min and at 25° C. for 18 h. After this time the reaction was concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(3-oxo-cyclobutyl)-propionamide (49 mg, 52%) as an off-white solid: [α]29589=−14.0° (c=0.55, CHCl3); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04, 1.05 (2×s, 6H, 2×CH3), 1.93-2.40 (m, 3H, CH and CH2), 2.69-2.84 (m, 2H, 2×CH or 2×CH2), 2.99-3.12 (m, 2H, 2×CH or 2×CH2), 3.14 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.88 (t, J=7.8 Hz, 1H, ArCHCO2), 3.98 (s, 2H, NCH2), 6.47 (d, J=2.3 Hz, 1H, Ar), 7.49 (d, J=2.3 Hz, 1H, Ar), 7.61 (dd, Jm=1.2 Hz, Jo=8.3 Hz, 1H, Ar), 7.73 (d, Jm=1.2 Hz, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1H, NH).

Workup

  1. concentrationAfter this time, the reaction was concentrated in vacuo
  2. customazeotroped with methylene chloride (10 ml)
  3. additionAfter addition
  4. stirringwas then stirred at 0° C. for 15 min and at 25° C. for 18 h
  5. concentrationAfter this time the reaction was concentrated in vacuo
  6. customPurification on an AnaLogix Intelliflash system (40 g column, 50% ethyl acetate/hexanes to 100% ethyl acetate)

Sources & evidence

ORD record
ord-7a6854c78fc04d0485353bcc6dead6d6
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

Loading…