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

HRID 546025Notes

Reaction equation

HRID 546025 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)=CC=CC=1C.[Cl:42][C:43]1[CH:55]=[CH:54][C:46](CN2C=CC(N)=N2)=[CH:45][CH:44]=1>C(Cl)Cl>[Cl:42][C:43]1[CH:55]=[CH:54][C:46]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)=[CH:45][CH:44]=1

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 6736901-(4-chlorobenzyl)-1H-pyrazol-3-amineHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole

Product 1

HCID 67188659N-[1-(4-chloro-benzyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamideYield 74.9%

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-chloro-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 N-[1-(4-chloro-benzyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (117 mg, 74%) as a white solid: ESI-LRMS m/e calcd for C25H27C12N3O3S [M+] 519.1, found 520.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.20 (m, 2H, CH2), 1.40-1.93 (m, 8H, 4×CH2), 2.09-2.31 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.51-3.60 (m, 1H, CH), 5.09 (s, 2H, NCH2), 6.69 (d, J=2.3 Hz, 1H, Ar), 7.06 (d, Jo=8.3 Hz, 2H, Ar), 7.26-7.33 (m, 3H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 7.88-8.36 (m, 2H, Ar and 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-ba1ae0ddaece44c689c2df9f0c9dd779
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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