2,6-Lutidine → HCID 24890164, compound

HRID 546242Notes

Reaction equation

HRID 546242 reaction equation
[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-olHCID 67189439HCID 67189439, compound

Product 1

HCID 24890164HCID 24890164, compoundYield 58%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

(R)-3-cyclopentyl-2-[4-(propane-2-sulfonyl)-phenyl]-propionic acid (100 mg, 0.31 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 180 μL, 0.33 mmol) which produced gas evolution and it was then stirred at 25° C. for 15 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (3 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 50 mg, 0.31 mmol), 2,6-lutidine (100 μL, 0.62 mmol) and methylene chloride (3 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 3 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride. It was then washed with 1 N aqueous hydrochloric acid solution and saturated aqueous brine solution dried over sodium sulfate and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 60% ethyl acetate/hexanes to 100% ethyl acetate) to afford (R)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(propane-2-sulfonyl)-phenyl]-propionamide (83 mg, 58%) as a white foam: [α]30589=−8.3° (c=0.18, methanol); ES-HRMS m/e calcd for C24H35N3O4S (M+H)+ 462.2421, observed 462.2421; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3 H, CH3), 1.11 (m, 2H, CH2), 1.13 (d, J=6.9 Hz, 6H, 2×CH3), 1.35-1.80 (m, 8H, 4×CH2), 2.10 (m, 1H, CH), 3.36 (m, 1H, SO2CH), 3.86 (s, 2H, NCH2), 3.93 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.46 (d, J=2.4 Hz, 1H, Ar), 7.50 (d, J=2.4 Hz, 1H, Ar), 7.64 (d, J=8.4 Hz, 2H, Ar), 7.80 (d, J=8.4 Hz, 2H, Ar), 10.79 (s, 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 (3 mL)
  5. temperatureto warm to 25° C.
  6. stirringstirred for 3 h
  7. customAfter this time, the reaction was quenched with a small amount of methanol
  8. additiondiluted with methylene chloride
  9. washIt was then washed with 1 N aqueous hydrochloric acid solution and saturated aqueous brine solution
  10. dry with materialdried over sodium sulfate
  11. concentrationconcentrated with silica gel (2 g) in vacuo
  12. custompurified on Biotage Flash chromatography system (40S column, silica gel, 60% ethyl acetate/hexanes to 100% ethyl acetate)

Sources & evidence

ORD record
ord-8acabfe0f87d46b2b0a25b3c7cee234a
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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