2,6-Lutidine → HCID 67189292, compound

HRID 546217Notes

Reaction equation

HRID 546217 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.[CH3:28][O:29][CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH3:28][O:29][CH2:30][CH2:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][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:33]1

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 451167281-(2-methoxyethyl)-1H-pyrazol-3-amineHCID 67189705HCID 67189705, compound

Product 1

HCID 67189292HCID 67189292, compoundYield 93.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (prepared in Example 118, 90 mg, 0.30 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, 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 100% ethyl acetate) to afford (R)—N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (79 mg, 62%) as a pale yellow gum: [α]29589=−79.3° (c=0.14, methanol); ES-HRMS m/e calcd for C21H24N3O3F3 (M+H)+ 424.1843, observed 424.1841; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.74-2.29 (m, 8H, 4×CH2), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.3 Hz, 2H, OCH2), 3.94 (m, 1H, ArCHCO), 4.12 (t, J=5.3 Hz, 2H, NCH2), 6.42 (d, J=2.2 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.60 (m, 2H, Ar), 7.69 (brd, 1H, Ar), 7.73 (brs, 1H, Ar), 10.80 (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 100% ethyl acetate)

Sources & evidence

ORD record
ord-ff740f20b04b4c408f61585774e47ae3
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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