2,6-Lutidine → HCID 67191201, compound

HRID 546082Notes

Reaction equation

HRID 546082 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.NC1C=CN(C[C:49]#[C:50][CH2:51][OH:52])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:49]#[C:50][CH2:51][OH:52])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazoleHCID 67189872HCID 67189872, compound

Product 1

HCID 67191201HCID 67191201, compoundYield 27.2%

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, 241 mg, 0.73 mmol) was suspended in methylene chloride (3.6 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (364 μL, 0.73 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (170 μL, 1.46 mmol) was added. The reaction continued to stir at 0° C. for 15 min. 4-(3-Amino-pyrazol-1-yl)-but-2-yn-1-ol (110 mg, 0.73 mmol) was dissolved in methylene chloride (3.6 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; 5% ethyl acetate/methylene chloride to 100% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-hydroxy-but-2-ynyl)-1H-pyrazol-3-yl]-propionamide (92 mg, 27%) as a white foam: ESI-LRMS m/e calcd for C22H26ClN3O4S [M+] 463.1, found 464.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.24 (m, 2H, CH2), 1.44-1.95 (m, 8H, 4×CH2), 2.10-2.37 (m, 1H, CH), 3.27 (s, 3H, SO2CH3), 3.56 (t, J=7.4 Hz, 1H, CH), 4.31 (t, J=1.7 Hz, 2H, OCH2), 4.82 (t, J=1.7 Hz, 2H, NCH2), 6.72 (d, Jo=2.3, 1H, Ar), 7.43 (d, Jo=2.3, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.4 Hz. 1H, Ar), 7.59 (d, Jm=1.4 Hz, 1H, Ar), 8.08 (brs, 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; 5% ethyl acetate/methylene chloride to 100% ethyl acetate/methylene chloride)

Sources & evidence

ORD record
ord-77f17ed54b484bb09837420c5b017769
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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