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

HRID 546006Notes

Reaction equation

HRID 546006 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.N1C(C)=CC=CC=1C.[NH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl>[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:25])[NH:46][CH2:47][CH2:48][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]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 4082852-MorpholinoethylamineHCID 671905033-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid

Product 1

HCID 671897172(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-{1-[2-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-1H-pyrazol-3-yl}-propionamideYield 27%

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, 4-(2-aminoethyl) morpholine (15 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-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-1H-pyrazol-3-yl}-propionamide (17 mg, 27%) as a white solid: ESI-LRMS m/e calcd for C27H38ClN5O5S [M+] 579.2, found 580.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.99-1.11 (m, 2H, CH2), 1.37-1.85 (m, 8H, 4×CH2), 2.05-2.18 (m, 1H, CH), 2.25-2.37 (m, 6H, 3×NCH2), 2.57 (t, J=6.4 Hz, 2H, COCH2), 3.18 (s, 3H, SO2CH3), 3.21 (q, J=5.4 Hz, 2H, CONCH2), 3.47 (t, J=7.5 Hz, 1H, CH), 3.50-3.58 (m, 4H, 2×OCH2), 4.23 (t, J=6.4 Hz, 2H, NCH2), 5.94 (brm, 1, NH), 6.50 (d, J=2.3 Hz, 1H, Ar), 7.22 (d, J=2.3 Hz, 1H, Ar), 7.38 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.51 (d, Jm=1.7 Hz, 1H, Ar), 7.84 (s, 1H, NH), 8.00 (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-520afc7f42c24e939366333ffe11fb3a
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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