2,6-Lutidine → HCID 67190037, compound

HRID 546156Notes

Reaction equation

HRID 546156 reaction equation
[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:12]([OH:14])=O)=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].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>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][N:32]1[CH:33]=[CH:34][C:30]([NH:29][C:12](=[O:14])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:31]1

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-olHCID 67188902HCID 67188902, compound

Product 1

HCID 67190037HCID 67190037, compoundYield 66%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

2(R)-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (75 mg, 0.23 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 120 μL, 0.24 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was concentrated in vacuo and the residue was then taken up in methylene chloride (2 mL). This solution was then added dropwise to a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 36 mg, 0.23 mmol), 2,6-lutidine (54 μL, 0.46 mmol), and methylene chloride (2 mL) which was cooled to 0° C. The reaction was allowed to warm to 25° C. and stirred for a period of 2 h. After this time, the reaction quenched with a small amount of methanol and then concentrated in vacuo. It was then dissolved in ethyl acetate (25 mL) and washed with a 1N hydrochloric acid solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 10% methanol/ethyl acetate) to afford N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (70 mg, 66%) as a white foam: [α]30589=−6.9° (c=0.16, methanol); ES-HRMS m/e calcd for C23H33N3O5S (M+H)+ 464.2214, observed 464.2208; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03, 1.04 (2×s, 6 H, 2×CH3), 1.07-1.43 (m, 3H, 3×CH of 2×CH2), 1.49-1.70 (m, 3H, 3×CH of 2×CH2), 1.98-2.12 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.14-3.25 (m, 2H, OCH2), 3.17 (s, 3H, SO2CH3), 3.73-3.83 (m, 2H, OCH2), 3.84 (s, 2H, NCH2), 3.90-3.99 (m, 1H, ArCH), 4.64 (s, 1H, OH), 6.43 (d, J=2.3 Hz, 1H, Ar), 7.41-7.46 (m, 2H, Ar), 7.48 (d, J=2.3 Hz, 1H, Ar),), 7.83 (d, J=8.5 Hz, 1H, Ar), 10.72 (s, 1H, NH)

Workup

  1. customat 25° C.
  2. customproduced gas evolution and it
  3. concentrationAfter this time, the reaction was concentrated in vacuo
  4. additionThis solution was then added dropwise to a flask
  5. temperaturewas cooled to 0° C
  6. temperatureto warm to 25° C.
  7. stirringstirred for a period of 2 h
  8. customAfter this time, the reaction quenched with a small amount of methanol
  9. concentrationconcentrated in vacuo
  10. dissolutionIt was then dissolved in ethyl acetate (25 mL)
  11. washwashed with a 1N hydrochloric acid solution (1×10 mL)
  12. dry with materialThe organic layer was then dried over sodium sulfate
  13. concentrationconcentrated with silica gel (2 g) in vacuo
  14. custompurified on Biotage Flash chromatography system (40S column, silica gel, 10% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-8321e48d22b44cbfa570ec96f10f9e44
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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