2,6-Lutidine → HCID 67189923, compound

HRID 546232Notes

Reaction equation

HRID 546232 reaction equation
[CH:1]1([CH2:5][C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([CH3:20])[CH:11]=2)[C:7]([OH:9])=O)[CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:5][C@H:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([CH3:20])[CH:11]=2)[C:7]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:2][CH2:3][CH2:4]1

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-olHCID 67193452HCID 67193452, compound

Product 1

HCID 67189923HCID 67189923, compoundYield 72%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

In a flask (R)-3-cyclobutyl-2-(4-methanesulfonyl-3-methyl-phenyl)-propionic acid (88 mg, 0.30 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 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-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 47 mg, 0.30 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with ethyl acetate (20 mL). This was then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and a saturated aqueous brine solution (10 mL). It was then dried over sodium sulfate, filtered and concentrated with silica gel (2 g) in vacuo and then purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate) to afford (R)-3-cyclobutyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 72%) as a white foam: [α]2958932 −14.7° (c=0.19, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.49-2.21 (m, 9 H, CH and 4×CH2), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.73 (m, 1H, ArCHCO), 3.86 (s, 2H, NCH2), 4.64 (s, 1H, OH), 6.44 (d, J=2.2 Hz, 1H, Ar), 7.42 (m, 2H, Ar), 7.50 (d, J=2.2 Hz, 1H, Ar), 7.84 (d, Jo=8.6 Hz, 1H, Ar), 10.70 (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 (2 mL)
  5. temperatureto warm to 25° C.
  6. stirringstirred for 1 h
  7. customAfter this time, the reaction was quenched with a small amount of methanol
  8. additiondiluted with ethyl acetate (20 mL)
  9. washThis was then washed with a 1 N aqueous hydrochloric acid solution (10 mL)
  10. dry with materialIt was then dried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated with silica gel (2 g) in vacuo
  13. custompurified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate)

Sources & evidence

ORD record
ord-47454f9eed224c039f7eef46b4fe441c
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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