Dichloromethane → HCID 42629215, compound

HRID 1643488Notes

Reaction equation

HRID 1643488 reaction equation
[F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[N:26]=[C:25]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)[CH2:32][CH2:31]2)=[O:28])[CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>CN(C=O)C.C(OCC)C.CO.C(Cl)Cl>[N:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:33]2[CH2:34][CH2:35][CH:30]([NH:29][C:27](=[O:28])[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:15][CH:12]4[CH2:13][CH2:14][N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=5)[CH2:10][CH2:11]4)[N:26]=3)[CH2:31][CH2:32]2)=[CH:42][CH:41]=1

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 24758Sodium hydride2×HCID 220976741-[4-(Trifluoromethyl)phenyl]piperidin-4-olHCID 86632134HCID 86632134, compound

Product 1

HCID 42629215HCID 42629215, compoundYield 25%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

To a solution of 1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.1 g, 0.4 mmol) in anhydrous DMF, NaH (60% in mineral oil, 18 mg, 0.45 mmol) was added. The mixture was allowed to stir at room temperature under N2 atmosphere for 10 min, followed by the addition of 6-chloro-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)picolinamide (0.15 g, 0.4 mmol). The resulting reaction mixture was then stirred with heating at 105° C. overnight. A significant amount of starting material was still present and hence, an additional amount of NaH was added (82 mg, 2.1 mmol). The reaction mixture was allowed to stir at 105° C. for an additional 8 h, and quenched with saturated sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL), and the combined organic layer was washed with water (2×20 mL) and brine (1×20 mL), dried (MgSO4), filtered and concentrated to give a yellow residue. Column chromatography (100% CH2Cl2→3% MeOH/CH2Cl2) provided a yellow solid, which upon trituration with ethyl ether, yielded N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide as a tan solid (54 mg, 25%). 1H NMR (CD3OD) δ 8.53 (d, J=4.1 Hz, 2H), 8.28 (d, J=7.4 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.51 (d, J=4.1 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.3 Hz, 2H), 6.96 (d, J=8.3 Hz, 1H), 5.43 (br s, 1H), 4.10-3.95 (m, 1H), 3.90 (s, 2H), 3.77-3.56 (m, 2H), 3.23-2.98 (m, 3H), 2.71-2.57 (m, 2H), 2.23-1.81 (m, 9H). MS (m/z): 540 (M+H)+.

Workup

  1. customThe resulting reaction mixture
  2. stirringwas then stirred
  3. temperaturewith heating at 105° C. overnight
  4. stirringto stir at 105° C. for an additional 8 h
  5. customquenched with saturated sodium bicarbonate solution (20 mL)
  6. extractionThe aqueous layer was extracted with ethyl acetate (3×20 mL)
  7. washthe combined organic layer was washed with water (2×20 mL) and brine (1×20 mL)
  8. dry with materialdried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto give a yellow residue

Sources & evidence

ORD record
ord-c1e10f5090e341e7b3c1fcd49681c552
Source dataset
uspto-grants-2012_02
Patent number
US08119809B2

Reaction notes

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