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

HRID 546073Notes

Reaction equation

HRID 546073 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](O)=[O:27])=[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.[NH2:51][CH2:52][CH2:53][CH2:54][OH:55]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H: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:23]=[CH:24][C:25]([C:26]([NH:51][CH2:52][CH2:53][CH2:54][OH:55])=[O:27])=[CH:29][CH:30]=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 90863-Amino-1-propanolHCID 65578Oxalyl chlorideHCID 671891864-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid

Product 1

HCID 671906604-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-hydroxy-propyl)-benzamideYield 32%

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. 3-Amino-propan-1-ol (7 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 preparative thin layer chromatography (Merck Silica gel 60 F254, 500 μm, 20×20 cm; 100% ethyl acetate) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-hydroxy-propyl)-benzamide (14 mg, 32%) as a white waxy solid: ESI-LRMS m/e calcd for C29H35ClN4O5S [M+] 586.2, found 587.29 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.22 (m, 2H, CH2), 1.43-1.93 (m, 10H, 5×CH2), 2.15-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.57-3.67 (m, 3H, CH2 and CH), 3.73 (t, J=5.5 Hz, 2H, CH2), 5.18 (s, 2H, NCH2), 6.74 (d, J=2.3 Hz, 1H, Ar), 6.82 (brm, 1H, NH), 7.12 (d, Jo=8.1 Hz, 2H, Ar), 7.36 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 7.67 (d, Jo=8.1 Hz, 2H, Ar), 8.04 (d, Jo=8.1 Hz, 1H, Ar), 8.32 (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-4eafcd9cabdc4069aff40fa7f319ded3
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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