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

HRID 546115

Reaction equation

HRID 546115 reaction equation
Cl[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](O)=[O:23])[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.[C:45]([Si:49]([CH3:60])([CH3:59])OCCN1C=CC(N)=N1)([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl>[C:45]([Si:49]([CH3:60])([CH3:59])[O:23][CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:3]=[CH:2][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:6][CH:5]=2)[CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[N:17]1)([CH3:48])([CH3:47])[CH3:46]

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449471-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamineHCID 67189335{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid

Product 1

HCID 67191478N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionamideYield 46.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

The 3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 3, 184 mg, 0.62 mmol) was dissolved in methylene chloride (3 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (31 μL, 0.62 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (144 μL, 1.24 mmol) was added dropwise. A strong exotherm and bubbling were observed. The solution continued to stir at 0° C. for 10 min. The 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 150 mg, 0.62 mmol) was added as a solution in methylene chloride (3 mL), the ice bath was removed and the solution continued to stir at 25° C. for 25 min. The solution 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; 40% ethyl acetate/hexanes) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionamide (150 mg, 44%) as a white foam: ESI-LRMS m/e calcd for C26H41N3O4SSi [M+] 519.26, found 520.36 [M+H+].

Workup

  1. temperatureThe solution was chilled to 0° C.
  2. customA strong exotherm and bubbling
  3. stirringto stir at 0° C. for 10 min
  4. customthe ice bath was removed
  5. stirringto stir at 25° C. for 25 min
  6. additionThe solution was diluted with methylene chloride (100 mL)
  7. washwashed with water (2×30 mL), saturated aqueous brine solution (1×20 mL)
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated in vacuo to a beige foam
  10. customPurification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-42826b67605949f9a962296cf5da4fad
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Linked notes

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