2,6-Lutidine → HCID 67190396, compound

HRID 546090Notes

Reaction equation

HRID 546090 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.[CH3:42][O:43][C:44](=[O:58])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47](CN2C=CC(N)=N2)[CH:46]=1>C(Cl)Cl>[CH3:42][O:43][C:44](=[O:58])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)[CH:46]=1

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole2×HCID 671899153-(3-Amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester

Product 1

HCID 67190396HCID 67190396, compoundYield 47.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (250 mg, 0.76 mmol, prepared as in PCT WO 2004/052869 A1, Example 1) was dissolved in methylene chloride (3.8 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (380 μL, 0.76 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (180 μL, 1.52 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (176 mg, 0.76 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (40 mL), washed with water (2×10 mL), saturated aqueous brine solution (1×10 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; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (196 mg, 47%) as a white foam: ESI-LRMS m/e calcd for C27H30ClN3O5S [M+] 543.16, found 544.22 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.21 (m, 2H, CH2), 1.45-1.94 (m, 8H, 4×CH2), 2.15-2.34 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.52 (t, J=7.5 Hz, 1H, CH), 3.91 (s, 3H, CO2CH3), 5.19 (s, 2H, NCH2), 6.72 (d, J=2.2 Hz, 1H, Ar), 7.34 (m, 2H, Ar), 7.40 (d, Jo=7.7 Hz, 1H, Ar), 7.44 (dd, Jo=8.3, Jm=1.5 Hz. 1H, Ar), 7.58 (d, Jm=1.5 Hz, 1H, Ar), 7.84-7.91 (m, 2H, Ar and NH), 7.97 (d, Jo=7.7 Hz, 1H, Ar), 8.08 (d, Jo=8.3 Hz, 1H, Ar).

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 25 min
  5. additionThe reaction was diluted with methylene chloride (40 mL)
  6. washwashed with water (2×10 mL), saturated aqueous brine solution (1×10 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; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride)

Sources & evidence

ORD record
ord-0283b41c577441eaa9f109bf4c4a69af
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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