2,6-Lutidine → HCID 67189161, compound

HRID 546059Notes

Reaction equation

HRID 546059 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].C(N1C=CC(N)=N1)CCCCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:41][CH2:35][CH2:36][CH2:37][CH3:38])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 60783142HCID 60783142, compoundHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole

Product 1

HCID 67189161HCID 67189161, compoundYield 68%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent4×

Conditions

Temperature
25 °C

Procedure

2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 174 mg, 0.53 mmol) was dissolved in methylene chloride and a 2.0 M solution of oxalyl chloride in methylene chloride (191 mg, 0.58 mmol) was added. The reaction stirred at 25° C. for 1 h. The reaction was chilled to 0° C. under nitrogen and 2,6-lutidine (140 μL, 1.21 mmol) was added dropwise. The reaction became golden brown, the ice bath was removed and the reaction continued to stir at 25° C. for 30 min. 1-Hexyl-1H-pyrazol-3-ylamine (88 mg, 0.53 mmol) was dissolved in methylene chloride and added dropwise to the reaction. The solution continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride, washed with water and saturated aqueous brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) to afford 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-hexyl-1H-pyrazol-3-yl)-propionamide as a white powder (171 mg, 68%) ESI-LRMS m/e calcd for C24H34ClN3O3S [M+] 479.2, found 480.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.88 (t, J=6.7 Hz, 3H, CH3), 1.08-1.21 (m, 2H, CH2), 1.24-1.37 (m, 6H, 3×CH2), 1.45-1.94 (m, 10H, 5×CH2), 2.09-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.6 Hz, 1H, CH), 3.96 (t, J=7.1 Hz, 2H, NCH2), 6.63 (d, J=2.3 Hz, 1H, Ar), 7.24 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.1, Jm=1.8 Hz. 1H, Ar), 7.59 (d, Jm=1.8 Hz, 1H, Ar), 7.82 (s, 1H, NH), 8.09 (d, Jo=8.1 Hz, 1H, Ar).

Workup

  1. temperatureThe reaction was chilled to 0° C. under nitrogen
  2. customthe ice bath was removed
  3. stirringto stir at 25° C. for 30 min
  4. additionadded dropwise to the reaction
  5. stirringto stir at 25° C. for 16 h
  6. washwashed with water and saturated aqueous brine solution
  7. dry with materialThe organic layer was dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-c3134cacf73e47b4ac1c6c0e5a0840b5
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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