2,6-Lutidine → HCID 67189002, compound

HRID 546216Notes

Reaction equation

HRID 546216 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.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[OH:37][C:35]([CH3:38])([CH3:36])[CH2:34][N:31]1[CH:32]=[CH:33][C:29]([NH:28][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:30]1

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-olHCID 67189705HCID 67189705, compound

Product 1

HCID 67189002HCID 67189002, compoundYield 64%

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-(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 (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-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (84 mg) which still contained impurities. This material was then cleaned up by using reverse phase HPLC. The purified material was then concentrated in vacuo then dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and then brine, dried over sodium sulfate and concentrated in vacuo to afford pure (R)—N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (53 mg, 40%) as a white foam: [α]29589=−67.5° (c=0.12, methanol); ES-HRMS m/e calcd for C22H26N3O3F3 (M+H)+ 438.1999, observed 438.1999; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.50 (m, 1H, CH), 1.73-2.30 (m, 8H, 4×CH2), 3.87 (s, 2H, NCH2), 3.95 (m, 1H, ArCHCO), 4.64 (s, 1H, OH), 6.46 (d, J=2.2 Hz, 1H, Ar), 7.50 (d, J=2.2 Hz, 1H, Ar), 7.60 (m, 2H, Ar), 7.69 (brd, 1H, Ar), 7.73 (brs, 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 100% ethyl acetate)

Sources & evidence

ORD record
ord-fb14594fdc734fc695749b567341cb42
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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