2,6-Lutidine → HCID 67190283, compound

HRID 546092Notes

Reaction equation

HRID 546092 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](NC2C=CN(C)N=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.[CH:42]([N:45]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46]1)([CH3:44])[CH3:43]>C(Cl)Cl>[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:50][C:47]2[CH:48]=[CH:49][N:45]([CH:42]([CH3:44])[CH3:43])[N:46]=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 65578Oxalyl chlorideHCID 195767971-(propan-2-yl)-1H-pyrazol-3-amineHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole

Product 1

HCID 67190283HCID 67190283, compoundYield 46%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

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, 302 mg, 0.91 mmol) was suspended in methylene chloride (4.5 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (456 μL, 0.91 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (212 μL, 1.82 mmol) was added. The reaction continued to stir at 0° C. for 15 min. 1-Isopropyl-1H-pyrazol-3-ylamine (114 mg, 0.91 mmol) was dissolved in methylene chloride (4.5 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (50 mL), washed with water (2×15 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to an orange foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-isopropyl-1H-pyrazol-3-yl)-propionamide (183 mg, 46%) as a white foam: ESI-LRMS m/e calcd for C21H28ClN3O3S [M+] 437.15, found 438.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.22 (m, 2H, CH2), 1.46 (d, J=6.6 Hz, 6H, 2×CH3), 1.44-1.94 (m, 8H, CH), 4×CH2), 2.11-2.32 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.5 Hz, 1H, CH), 4.33 (sept, J=6.6 Hz, 1H, NCH), 6.64 (d, Jo=2.3, 1H, Ar), 7.30 (d, Jo=2.3, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.60 (d, Jm=1.6 Hz, 1H, Ar), 7.86 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).

Workup

  1. temperatureThe solution was chilled to 0° C.
  2. stirringto stir at 0° C. for 15 min
  3. additionadded dropwise to the reaction
  4. customThe ice bath was removed
  5. stirringto stir at 25° C. for 30 min
  6. additionThe reaction was diluted with ethyl acetate (50 mL)
  7. washwashed with water (2×15 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), saturated aqueous brine solution (10 mL)
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated in vacuo to an orange foam
  10. customPurification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride)

Sources & evidence

ORD record
ord-14346676831b43b0b5e78a0881d1c1aa
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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