2,6-Lutidine → HCID 67192710, compound

HRID 546077Notes

Reaction equation

HRID 546077 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.NC1C=CN(C[CH2:49][C:50]([CH3:53])([OH:52])[CH3:51])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][CH2:49][C:50]([OH:52])([CH3:53])[CH3:51])[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 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazoleHCID 671912664-(3-Aminopyrazol-1-yl)-2-methylbutan-2-ol

Product 1

HCID 67192710HCID 67192710, compoundYield 54.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent4×

Conditions

Temperature
25 °C

Procedure

2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 825 mg, 2.50 mmol) was suspended in methylene chloride (12.5 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (1.25 mL, 2.5 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (582 μL, 5.00 mmol) was added. The reaction continued to stir at 0° C. for 10 min. 4-(3-Amino-pyrazol-1-yl)-2-methyl-butan-2-ol (424 mg, 2.50 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to the reaction. The reaction continued to stir at 0° C. for 10 min. The reaction was diluted with methylene chloride (50 mL), washed with water (15 mL), saturated aqueous brine solution (10 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 35% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-3-methyl-butyl)-1H-pyrazol-3-yl]-propionamide (653 mg, 54%) as a white foamy solid: ESI-LRMS m/e calcd for C23H32ClN3O4S [M+] 481.18, found 482.35 [M+H+], 464.22 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.23 (m, 2H, CH2), 1.29 (s, 6H, 2×CH3), 1.46-1.94 (m, 8H, 4×CH2), 1.94-2.04 (m, 2 H, CH2), 2.18-2.29 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.55 (t, J=7.5 Hz, 1H, CH), 3.00-4.25 (m, 2H, NCH2), 6.65 (d, J=2.3 Hz, 1H, Ar), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.47 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.61 (d, Jm=1.7 Hz, 1H, Ar), 8.10 (d, Jo=8.2 Hz, 1H, Ar), 8.12 (s, 1H, NH).

Workup

  1. temperatureThe solution was chilled to 0° C.
  2. stirringto stir at 0° C. for 10 min
  3. additionadded dropwise to the reaction
  4. stirringto stir at 0° C. for 10 min
  5. washwashed with water (15 mL), saturated aqueous brine solution (10 mL), 1.0 M aqueous hydrochloric acid solution (10 mL)
  6. dry with materialdried over magnesium sulfate
  7. concentrationconcentrated in vacuo
  8. customto give a yellow oil
  9. customPurification by flash column chromatography (Merck silica gel 60, 40-63 μm; 35% ethyl acetate/methylene chloride)

Sources & evidence

ORD record
ord-35e5b65110ce434daf824715730ba48f
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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