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

HRID 546003Notes

Reaction equation

HRID 546003 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](O)=[O:24])[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.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>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]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:24])[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 8083MorpholineHCID 65578Oxalyl chlorideHCID 671905033-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid

Product 1

HCID 671883352(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-morpholin-4-yl-3-oxo-propyl)-1H-pyrazol-3-yl]-propionamideYield 30%

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, morpholine (10 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-(3-morpholin-4-yl-3-oxo-propyl)-1H-pyrazol-3-yl]-propionamide (17 mg, 30%) as a white solid: ESI-LRMS m/e calcd for C25H33ClN4O5S [M+] 536.2, found 537.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.22 (m, 2H, CH2), 1.44-1.93 (m, 8H, 4×CH2), 2.12-2.30 (m, 1H, CH), 2.79 (t, J=6.6 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.31-3.41 (m, 2H, CH2), 3.53 (t, J=7.6 Hz, 1H, CH), 3.55-3.66 (m, 6H, 3×CH2), 4.35 (t, J=6.6 Hz, 2H, NCH2), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.35 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.75 (s, 1H, 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-daa60096190d47229d39a7b6e2d52331
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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