2,6-Lutidine → HCID 10029454, compound

HRID 854754Notes

Reaction equation

HRID 854754 reaction equation
[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:12]([OH:14])=O)=[CH:7][C:6]=1[C:22]([F:25])([F:24])[F:23])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[CH3:32][O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37][CH:36]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH3:32][O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:12](=[O:14])[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([C:22]([F:23])([F:25])[F:24])[CH:7]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[N:37][CH:36]=1

Participants

9

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 737487Methyl 6-aminonicotinateHCID 21958991HCID 21958991, compound

Product 1

HCID 10029454HCID 10029454, compoundYield 55.8%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (prepared as in Example 12, 300 mg, 0.79 mmol) in methylene chloride (6 mL) was treated with N,N-dimethylformamide (7 drops) and then cooled to 0° C. The reaction mixture was then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.48 mL, 0.95 mmol). The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to 25° C., and then concentrated in vacuo to remove solvents and excess oxalyl chloride. The resulting residue was re-dissolved in dry tetrahydrofuran (6 mL) and was treated dropwise with a solution of 6-aminonicotinic acid methyl ester (252 mg, 1.67 mmol) in tetrahydrofuran (5 mL) and 2,6-lutidine (0.48 mL, 3.95 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (100 mL) and extracted with methylene chloride 3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 7/3 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid methyl ester (227 mg, 55%) as a white foam: EI-HRMS m/e calcd for C23H25F3N2O6S (M+H)+ 537.1277. found 537.1284.

Workup

  1. temperatureto warm to 25° C.
  2. concentrationconcentrated in vacuo
  3. customto remove solvents and excess oxalyl chloride
  4. dissolutionThe resulting residue was re-dissolved in dry tetrahydrofuran (6 mL)
  5. customThe resulting reaction mixture
  6. stirringwas stirred at 25° C. for 16 h
  7. extractionextracted with methylene chloride 3×50 mL)
  8. dry with materialThe combined organic layers were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-bd66dce3e5eb4bb68769e0b5bf4b3908
Source dataset
uspto-grants-2007_08
Patent number
US07259166B2

Reaction notes

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