2,6-Lutidine → HCID 67188835, compound

HRID 546214Notes

Reaction equation

HRID 546214 reaction equation
[O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1)([CH3:31])([CH3:30])[CH3:29].N1C(C)=CC=CC=1C>C(Cl)Cl>[C:28]([Si:32]([CH3:43])([CH3:42])[O:33][CH2:34][CH2:35][N:36]1[CH:40]=[CH:39][C:38]([NH:41][C:9](=[O:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7][C@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[N:37]1)([CH3:31])([CH3:30])[CH3:29]

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449471-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamineHCID 67189705HCID 67189705, compound

Product 1

HCID 67188835HCID 67188835, compoundYield 58%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (85 mg, 0.28 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 150 μL, 0.29 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 68 mg, 0.28 mmol), 2,6-lutidine (66 μL, 0.56 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1.5 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (85 mg, 57%) as a yellow oil: [α]25589=−9.4° (c=0.16, methanol); ES-HRMS m/e calcd for C26H36N3O3SiF3 (M+Na)+ 546.2370, observed 546.2367; 1H NMR (300 MHz, CDCl3) δ-0.06 (s, 6H, 2×SiCH3), 0.83 (s, 9H, 3×CH3), 1.57 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 3.57 (m, 1H, ArCHCO), 3.85 (t, J=5.3 Hz, 2H, OCH2), 4.05 (t, J=5.3 Hz, 2H, NCH2), 6.64 (d, J=2.2 Hz, 1H, Ar), 7.32 (d, J=2.2 Hz, 1H, Ar), 7.46-7.62 (m, 4H, Ar), 7.67 (brs, 1H, NH).

Workup

  1. customat 25° C.
  2. customproduced gas evolution and it
  3. concentrationwas concentrated in vacuo
  4. dissolutionThe residue was then dissolved in methylene chloride (2 mL)
  5. temperatureto warm to 25° C.
  6. stirringstirred for 1.5 h
  7. customAfter this time, the reaction was quenched with a small amount of methanol
  8. concentrationconcentrated with silica gel (2 g) in vacuo
  9. custompurified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-0336d71e3c4a43808b1f1c40f9a75b62
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

Loading…