2,6-Lutidine → 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-dimethylamino-propyl)-benzamide

HRID 546074Notes

Reaction equation

HRID 546074 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.N1C(C)=CC=CC=1C.[CH3:51][N:52]([CH2:54][CH2:55][CH2:56][NH2:57])[CH3:53]>C(Cl)Cl>[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]([NH:57][CH2:56][CH2:55][CH2:54][N:52]([CH3:53])[CH3:51])=[O:28])=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 7993N,N-Dimethyl-1,3-propanediamineHCID 65578Oxalyl chlorideHCID 671891864-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid

Product 1

HCID 671914164-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-dimethylamino-propyl)-benzamideYield 6.5%

Reagents, catalysts & solvents 1

HCID 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, 40 mg, 0.08 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (38 μL, 0.08 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (18 μL, 0.15 mmol) was added. The reaction continued to stir at 0° C. for 20 min. N,N-Di-methyl-3-amino-propyl-amine (12 μL, 0.09 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) followed by flash column chromatography (Merck silica gel 60, 40-63 μm; 0.5% ammonium hydroxide/methanol) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-dimethylamino-propyl)-benzamide (3 mg, 6.5%) as a clear oil: ESI-LRMS m/e calcd for C31H40ClN5O4S [M+] 613.25, found 614.21 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.24 (m, 2H, CH2), 1.44-1.94 (m, 8H, 4×CH2), 2.10-2.32 (m, 3H, CH), 2.78 (s, 6H, 2×NCH3), 3.06 (t, J=6.4 Hz, 2H, NCH2), 3.25 (s, 3H, SO2CH3), 3.56-3.66 (m, 2H, CH2), 3.69 (t, J=7.6 Hz, 1H, CH), 5.15 (s, 2H, NCH2), 6.72 (d, J=2.3 Hz, 1H, Ar), 7.13 (d, Jo=8.1 Hz, 2H, Ar), 7.33 (d, J=2.3 Hz, 1H, Ar), 7.49 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.65 (d, Jm=1.6 Hz, 1H, Ar), 7.91 (d, Jo=8.1 Hz, 2H, Ar), 8.05 (d, Jo=8.1 Hz, 1H, Ar), 8.37 (brm, 1H, NH), 8.59 (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 16 h
  5. additionThe reaction was diluted with methylene chloride (10 mL)
  6. washwashed with water (2×4 mL), saturated aqueous brine solution (1×4 mL)
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated in vacuo to a beige foam
  9. customPurification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run)

Sources & evidence

ORD record
ord-a3118af32fb74aa4a9b4302e830cbae2
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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