2,6-Lutidine → HCID 67190356, compound

HRID 546225Notes

Reaction equation

HRID 546225 reaction equation
[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[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.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12]([NH:38][C:35]2[CH:36]=[CH:37][N:33]([CH2:32][CH2:31][O:30][CH3:29])[N:34]=2)=[O:14])=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3]

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 451167281-(2-methoxyethyl)-1H-pyrazol-3-amineHCID 67191851HCID 67191851, compound

Product 1

HCID 67190356HCID 67190356, compoundYield 135.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

(R)-2-(4-Methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (prepared in Example 122, 97 mg, 0.30 mmol) was dissolved in methylene chloride (3 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, 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 (3 mL) and added dropwise into a solution of 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared in Example 72, 42 mg, 0.20 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (3 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 methylene chloride 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 5% methanol/ethyl acetate) to afford (R)-2-(4-methanesulfonyl-3-methyl-phenyl)-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (121 mg, 90%) as a colorless gum: [α]30589=−53.5° (c=0.17, methanol); ES-HRMS m/e calcd for C22H29N3O5S (M+H)+ 448.1901, observed 448.1900; 1H NMR (300 MHz, DMSO-d6) δ 1.50 (m, 1H, CH), 1.75-2.30 (m, 8H, 4×CH2), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, OCH3), 3.19 (s, 3H, SO2CH3), 3.61 (t, J=5.3 Hz, 2H, OCH2), 3.90 (m, 1H, ArCHCO), 4.11 (t, J=5.3 Hz, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.45 (brs, 1H, Ar), 7.47 (brd, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.85 (d, Jo=8.6 Hz, 1H, 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 1 h
  7. customAfter this time, the reaction was quenched with a small amount of methanol
  8. additiondiluted with methylene chloride
  9. concentrationconcentrated with silica gel (2 g) in vacuo
  10. custompurified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 5% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-aadaa42beca14d73b05fae3edfde03ab
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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