2,6-Lutidine → 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-methyl-benzyl)-1H-pyrazol-3-yl]-propionamide

HRID 546031Notes

Reaction equation

HRID 546031 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.N1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].CC1C=CC(CN2C=CC(N)=N2)=CC=1>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][C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:35]=3)[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 5710391-(4-Methylbenzyl)-1H-pyrazol-3-amineHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole

Product 1

HCID 671884852(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-methyl-benzyl)-1H-pyrazol-3-yl]-propionamideYield 57.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 1-(4-methyl-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-methyl-benzyl)-1H-pyrazol-3-yl]-propionamide (86 mg, 57%) as a white solid: ESI-LRMS m/e calcd for C26H30ClN3O3S [M+] 499.2, found 500.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.19 (m, 2H, CH2), 1.41-1.95 (m, 8H, 4×CH2), 2.10-2.27 (m, 1H, CH), 2.32 (s, 3H, ArCH3), 3.24 (s, 3H, SO2CH3), 3.55 (t, J=7.6 Hz, 1H, CH), 5.07 (s, 2H, NCH2), 6.67 (d, J=2.3 Hz, 1H, Ar), 7.04 (d, Jo=8.1 Hz, 2H, Ar), 7.11 (d, Jo=8.1 Hz, 2H, Ar), 7.26 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 8.04 (d, Jo=8.2 Hz, 1H, Ar), 8.31 (s, 1H, NH).

Workup

  1. waitAfter 1 h
  2. waitto proceed for 16 h
  3. washThe reaction solution was washed with 1.0 M aqueous hydrochloric acid solution
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. custompurified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride)

Sources & evidence

ORD record
ord-96c487765aa140ffa504d3e757010219
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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