2,6-Lutidine → HCID 67190207, compound

HRID 546243Notes

Reaction equation

HRID 546243 reaction equation
C(OC(=O)NC1C=CC=C([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31](Cl)[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)C=1)(C)(C)C.[C:42](Cl)(=[O:46])[C:43](Cl)=[O:44].N1C(C)=CC=C[C:49]=1C>C(Cl)Cl.CN(C)C=O>[CH:24]1([CH2:23][C@H:22]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:31]([CH3:49])[CH:30]=2)[C:21]([NH:20][C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:42]([OH:46])[CH2:43][OH:44])[N:16]=2)=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28]1

Participants

6

Reactant 3

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 67190452HCID 67190452, compound

Product 1

HCID 67190207HCID 67190207, compoundYield 42%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent5×

Conditions

Temperature
0 °C

Procedure

A solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 57, 360 mg, 1.16 mmol) was dissolved in methylene chloride (8 mL) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 640 μL, 1.27 mmol) and N,N-dimethylformamide (one drop) and it was then stirred at 0° C. for 20 minutes and 30 minutes at 25° C. After this time, the reaction was concentrated in vacuo. In a separate flask a solution of 3-(3-amino-pyrazol-1-yl)-propane-(R)-1,2-diol (prepared as in Example 35, 200 mg, 1.27 mmol), 2,6-lutidine (200 μL, 1.74 mmol) and methylene chloride (6 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 (8 mL) dropwise. After addition was complete the reaction was stirred at 0° C. for 30 minutes then allowed to warm to 25° C. and stirred for 18 h. After this time the reaction was diluted with methylene chloride (20 mL) and washed with a saturated aqueous sodium bicarbonate solution (20 mL) and a 1 N aqueous hydrochloric acid solution (20 mL). Each aqueous phase was backextracted with ethyl acetate (30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification an AnaLogix Intelliflash system (80 g column, 100% ethyl acetate) afforded (R)-3-cyclopentyl-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (220 mg, 42%) as an off-white solid: [α]30589=+5.80° (c=0.65, methanol); ES-HRMS m/e calcd for C22H31N3O5S (M+H)+ 450.2057, observed 450.2057; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09 (m, 2H, CH2), 1.33-1.81 (m, 8H, 4×CH2), 2.10 (m, 1H, CH), 2.61 (s, 3H, ArCH3), 3.17 (s, 3 H, SO2CH3), 3.26 (s, 2H, OCH2), 3.72 (brm, 1H, OCH), 3.82 (dd, J=7.6 Hz, 13.5 Hz, 1H, NCH of NCH2), 3.83 (m, 1H, ArCHCO), 4.05 (dd, J=4.0 Hz, 13.5 Hz, 1H, NCH of NCH2), 4.70 (t, J=5.6 Hz, 1H, OH), 4.92 (d, J=5.3 Hz, 1H, OH), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.44 (m, 2H, Ar), 7.50 (d, J=2.3 Hz, 1H, Ar), 7.84 (d, Jo=8.7 Hz, 1H, Ar), 10.74 (s, 1H, NH).

Workup

  1. concentrationAfter this time, the reaction was concentrated in vacuo
  2. additionAfter addition
  3. stirringwas stirred at 0° C. for 30 minutes
  4. temperatureto warm to 25° C.
  5. stirringstirred for 18 h
  6. washwashed with a saturated aqueous sodium bicarbonate solution (20 mL)
  7. dry with materialThe combined organic layers were dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification an AnaLogix Intelliflash system (80 g column, 100% ethyl acetate)

Sources & evidence

ORD record
ord-a808aa7c135b49099b09815f3d5d89ac
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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