Methylamine → 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide

HRID 546000Notes

Reaction equation

HRID 546000 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[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.[N:38]1C(C)=CC=C[C:39]=1C.CN.O1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:38][CH3:39])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]

Participants

7

Reactant 5

HCID 6329MethylamineHCID 79372,6-LutidineHCID 8028TetrahydrofuranHCID 65578Oxalyl chlorideHCID 671905033-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid

Product 1

HCID 671891222(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamideYield 21%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, a 2.0 M solution of methylamine in tetrahydrofuran (59 μL, 0.11 mmol) 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-(2-methylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide (11 mg, 21%) as a white solid: ESI-LRMS m/e calcd for C22H29ClN4O4S [M+] 480.2, found 481.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.20 (m, 2H, CH2), 1.46-1.96 (m, 8H, 4×CH2), 2.17-2.29 (m, 1H, CH), 2.62 (t, J=6.3 Hz, 2H, COCH2), 2.75 (d, J=4.9 Hz, 3H, CONCH3), 3.27 (s, 3H, SO2CH3), 3.55 (t, J=7.6 Hz, 1H, CH), 4.31 (t, J=6.3 Hz, 2H, NCH2), 5.48 (brm, 1H, NH), 6.58 (d, J=2.3 Hz, 1H, Ar), 7.30 (d, J=2.3 Hz, 1 H, Ar), 7.46 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.60 (d, Jm=1.6 Hz, 1H, Ar), 7.88 (s, 1 H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).

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-54fdab8fc4aa4ef78ac2a7c7a98d3bbe
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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