2,6-Lutidine → N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide

HRID 546130

Reaktionsgleichung

Reaktionsgleichung von HRID 546130
[C:1]([CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21]([Cl:29])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6]1)(=[O:3])N.C(Cl)(=O)C(Cl)=[O:33].N1C(C)=CC=CC=1C.[C:45]([Si:49]([CH3:60])([CH3:59])OCCN1C=CC(N)=N1)([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.CO>[C:45]([Si:49]([CH3:60])([CH3:59])[O:3][CH2:1][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[C:21]([Cl:29])[CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][O:33][CH2:16][CH2:15]2)=[N:6]1)([CH3:48])([CH3:47])[CH3:46]

Komponenten

7

Edukt 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449471-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamineHCID 67190535N-(1-Carbamoylmethyl-1H-pyrazol-3-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide

Produkt 1

HCID 67188252N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamideAusbeute 67 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 6344DichloromethaneLösungsmittel4×

Reaktionsbedingungen

Temperatur
25 °C

Versuchsvorschrift

A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (prepared as in PCT WO 2003/095438 A1, Example 20, 144 mg, 0.41 mmol) was dissolved in methylene chloride (4 mL) and N,N-dimethylfomamide (three drops) at 25° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 0.21 mL, 0.43 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (100 μL, 0.83 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 100 mg, 0.41 mmol) in methylene chloride (2 mL) and the reaction was allowed to warm up to 25° C. and stirred for 1 h. After this time the reaction was diluted with a small amount of methanol in methylene chloride and washed with aqueous 1 N hydrochloric acid solution and then a saturated aqueous brine solution/water reaction (1/1). Flash chromatography using Biotage system (40S column, Silica gel, 50% ethyl acetate/hexanes) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (158 mg, 67%) as an off-white foam: ES-HRMS m/e calcd for C26H40N3O5SSiCl (M+H)+ 570.2219, observed 570.2210; 1H NMR (400 MHz, DMSO-d6) δ ppm −0.08 (s, 6H, 2×SiCH3), 0.78 (s, 9H, 3×CH3), 1.13-1.27 (m, 2H, CH2), 1.29-1.43 (m, 1H, CH of CH2), 1.50-1.71 (m, 3H, CH of CH2 and CH2), 2.01-2.12 (m, 1H, CH), 3.20 (m, 2H, OCH2), 3.34 (s, 3H, SO2CH3), 3.76-3.88 (m, 4 H, OCH2 and SiOCH2), 3.97-4.10 (m, 3H, CH and NCH2), 6.42 (d, J=2.3 Hz, 1H, Ar), 7.53 (d, J=2.3 Hz, 1H, Ar), 7.60 (dd, Jo=8.2 Hz, Jm=1.6 Hz, 1H, Ar), 7.71 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.81 (s, 1H, NH).

Aufarbeitung

  1. customat 25° C
  2. customproduced gas evolution and it
  3. temperatureAfter this time, the reaction was cooled to 0° C.
  4. stirringwas stirred for 15 min
  5. temperatureto warm up to 25° C.
  6. stirringstirred for 1 h
  7. washwashed with aqueous 1 N hydrochloric acid solution
  8. customa saturated aqueous brine solution/water reaction (1/1)

Quellen und Nachweise

ORD-Eintrag
ord-66453570ee444321957674fd3e278205
Quelldatensatz
uspto-grants-2011_05
Patentnummer
US07935699B2

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