2,6-Lutidine → 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide

HRID 546118Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 546118
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:31](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.COCCN1C=CC(N)=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][O:24][CH3:31])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]

Komponenten

6

Edukt 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 451167281-(2-methoxyethyl)-1H-pyrazol-3-amineHCID 67189335{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid

Produkt 1

HCID 671906362-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamideAusbeute 41 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel3×

Reaktionsbedingungen

Temperatur
25 °C

Versuchsvorschrift

2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 469 mg, 1.42 mmol,) was suspended in methylene chloride (7 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (710 mL, 1.42 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (331 μL, 2.84 mmol) was added dropwise. The reaction continued to stir at 0° C. for 10 min. The 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (200 mg, 1.42 mmol) was added as a pre-dissolved reaction in methylene chloride (7 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 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 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (262 mg, 41%) as a white powder: ESI-LRMS m/e calcd for C21H28ClN3O4S [M+] 453.15, found 454.26 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.23 (m, 2H, CH2), 1.45-1.92 (m, 8H, 4×CH2), 2.14-2.33 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.31 (s, 3H, OCH3), 3.53 (t, J=7.6 Hz, 1H, CH), 3.67 (t, J=5.2 Hz, 2H, OCH2), 4.13 (t, J=5.2 Hz, 2H, NCH2), 6.65 (d, Jo=2.3 Hz, 1H, Ar), 7.33 (d, Jo=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1H, Ar), 7.81 (s, 1 H, NH), 8.08 (d, Jo=8.2 Hz, 1H, Ar).

Aufarbeitung

  1. temperatureThe solution was chilled to 0° C.
  2. stirringto stir at 0° C. for 10 min
  3. customthe ice bath was removed
  4. stirringto stir at 25° C. for 25 min
  5. additionThe reaction was diluted with methylene chloride (100 mL)
  6. washwashed with water (2×30 mL), saturated aqueous brine solution (1×20 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 20% ethyl acetate/methylene chloride)

Quellen und Nachweise

ORD-Eintrag
ord-4318848fa8b94fa495d345fb70c9b775
Quelldatensatz
uspto-grants-2011_05
Patentnummer
US07935699B2

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