2,6-Lutidine → 4-{3-[2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzamide

HRID 546071Notes

Reaction equation

HRID 546071 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[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:43]1C(C)=CC=CC=1C>C(Cl)Cl.[OH-].[NH4+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:43])=[O:28])=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]

Participants

6

Reactant 3

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 671891864-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid

Product 1

HCID 671885734-{3-[2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzamideYield 49%

Reagents, catalysts & solvents 2

HCID 14923Ammonium HydroxideCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 100 mg, 0.19 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (100 μL, 0.20 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (44 μL, 0.38 mmol) was added. The reaction continued to stir at 0° C. for 20 min. Concentrated aqueous ammonium hydroxide (4 drops) was added. The ice bath was removed and the reaction continued to stir at 25° C. for 20 min. The reaction was diluted with ethyl acetate (20 mL), washed with water (2×5 mL), saturated aqueous brine solution (1×5 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 4-{3-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzamide (49 mg, 49%) as an off white powder: ESI-LRMS m/e calcd for C26H29ClN4O4S [M+] 528.16, found 529.19 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.20 (m, 2H, CH2), 1.35-1.92 (m, 8H, 4×CH2), 2.11-2.26 (m, 1H, CH), 3.23 (s, 3H, SO2CH3), 3.65 (t, J=7.6 Hz, 1H, CH), 5.18 (s, 2H, NCH2), 6.08 (br.s., 2H, NH2), 6.74 (d, J=2.0 Hz, 1H, Ar), 7.15 (d, Jo=8.1 Hz, 2H, Ar), 7.37 (d, J=2.0 Hz, 1H, Ar), 7.43 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 7.72 (d, Jo=8.1 Hz, 2H, Ar), 7.98 (d, Jo=8.1 Hz, 1H, Ar), 8.79 (s, 1H, NH).

Workup

  1. temperatureThe solution was chilled to 0° C.
  2. stirringto stir at 0° C. for 20 min
  3. customThe ice bath was removed
  4. stirringto stir at 25° C. for 20 min
  5. additionThe reaction was diluted with ethyl acetate (20 mL)
  6. washwashed with water (2×5 mL), saturated aqueous brine solution (1×5 mL)
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated in vacuo to a beige foam
  9. customPurification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes to 100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-92f3487fe3c44b0e99f80b03c401a93a
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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