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

HRID 546019Notes

Reaction equation

HRID 546019 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:28](Cl)(=O)[C:29](Cl)=[O:30].N1C(C)=CC=CC=1C.NC1C=CN(CCCO)N=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][CH2:28][CH2:29][OH:30])[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 509897073-(3-amino-1H-pyrazol-1-yl)propan-1-olHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole

Product 1

HCID 248896672(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamideYield 34%

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, 3-(3-amino-pyrazol-1-yl)-propan-1-ol (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-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (47 mg, 34%) as a white solid: ESI-LRMS m/e calcd for C21H28ClN3O4S [M+] 453.15, found 454.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.02-1.21 (m, 2H, CH2), 1.40-1.92 (m, 8H, 4×CH2), 1.92-2.02 (m, 2H, CH2), 2.11-2.28 (m, 1H, CH), 2.88 (brs, 1H, OH), 3.26 (s, 3H, SO2CH3), 3.50-3.67 (m, 3H, OCH2 and CH), 4.11 (t, J=6.4 Hz, 2H, NCH2), 6.63 (d, Jo=2.3, 1H, Ar), 7.26 (d, Jo=2.3, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.58 (d, Jm=1.6 Hz, 1H, Ar), 8.05 (d, Jo=8.2 Hz, 1H, Ar), 8.38 (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-018d2fac33994f51b7454f7eecaaaf7c
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

Loading…