2,6-Lutidine → HCID 67189315, compound

HRID 546261Notes

Reaction equation

HRID 546261 reaction equation
[CH:1]1([CH2:6][CH:7]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]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>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[CH:12]=2)[C:8]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-olHCID 67192009HCID 67192009, compound

Product 1

HCID 67189315HCID 67189315, compoundYield 63%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent5×

Conditions

Temperature
0 °C

Procedure

A solution of 3-cyclopentyl-2-(1,1-dioxo-2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid (114 mg, 0.37 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 212 μL, 0.43 mmol) which produced gas evolution and it was stirred at 0° C. for 15 min and it was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to ˜1.5 mL. In a separate flask, a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 63 mg, 0.41 mmol), 2,6-lutidine (61 μL, 0.55 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (1 mL), dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (15 mL). The aqueous layer was then extracted with methylene chloride (2×10 mL). The organic layers were then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification using reverse phase HPLC afforded 3-cyclopentyl-2-(1,1-dioxo-2,3-dihydro-benzo[b]thiophen-5-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (103 mg, 63%) as a white foam (as a racemic mixture): ES-HRMS m/e calcd for C23H31N3O4S (M+H)+ 446.2108, observed 446.2109; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3 H, CH3), 1.10 (m, 2H, CH2), 1.38-1.79 (m, 8H, 4×CH2), 2.07 (m, 1H, CH), 3.33 (t, J=6.8 Hz, 2H, ArCH2), 3.56 (t, J=6.8 Hz, 2H, SO2CH2), 3.86 (s, 2 H, NCH2), 3.91 (m, 1 H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.51 (m, 3H, Ar), 7.69 (d, Jo=8.5 Hz, 1H, Ar), 10.75 (s, 1H, NH).

Workup

  1. customproduced gas evolution and it
  2. temperatureto warm to 25° C.
  3. stirringstirred for 1 h
  4. concentrationAfter this time, the reaction was concentrated in vacuo to ˜1.5 mL
  5. additionAfter addition
  6. temperatureto warm to 25° C.
  7. stirringstirred for 16 hours
  8. washwashed with a saturated aqueous sodium bicarbonate solution (15 mL)
  9. extractionThe aqueous layer was then extracted with methylene chloride (2×10 mL)
  10. washThe organic layers were then washed with a 1 N aqueous hydrochloric acid solution (10 mL)
  11. dry with materialdried over magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customPurification

Sources & evidence

ORD record
ord-7d20e863239943f686decf87fe624613
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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