4-Methylmorpholine → 7-chloro-1-{1-[(5'-fluoro-2'-{[(1R)-3-hydroxy-1-methylpropyl]oxy}-3-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one

HRID 1026588Notes

Reaction equation

HRID 1026588 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C@H:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([CH2:36][C:37]([CH3:50])([CH3:49])[C:38](=[O:48])[N:39]2[CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[N:34][CH:33]=1.CN1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C(Cl)Cl.CO.O1CCCC1>[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([CH2:36][C:37]([CH3:50])([CH3:49])[C:38](=[O:48])[N:39]2[CH:42]2[CH2:43][CH2:44][N:45]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:18][C@H:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:9][C:10]=3[CH3:17])=[O:15])[CH2:46][CH2:47]2)=[N:34][CH:33]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 27340594-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlorideHCID 680061317-chloro-3,3-dimethyl-1-piperidin-4-yl-3,4-dihydro-1,5-naphthyridin-2(1H)-one trifluoroacetateHCID 680063405'-fluoro-2'-{[(1R)-3-hydroxy-1-methylpropyl]oxy}-3-methylbiphenyl-4-carboxylic acid

Product 1

HCID 680060717-chloro-1-{1-[(5'-fluoro-2'-{[(1R)-3-hydroxy-1-methylpropyl]oxy}-3-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-oneYield 69%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21899815MeOH tetrahydrofuranSolvent

Procedure

To a methanol-tetrahydrofuran (1:1) mixed solvent solution (20.0 ml) of 5′-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}-3-methylbiphenyl-4-carboxylic acid (637 mg) and 7-chloro-3,3-dimethyl-1-piperidin-4-yl-3,4-dihydro-1,5-naphthyridin-2(1H)-one trifluoroacetate (Reference Example 10) (876 mg) were added at room temperature N-methylmorpholine (0.660 ml) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (940 mg), followed by stirring for 1 hour. The reaction solution was diluted with methylene chloride, then washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 7-chloro-1-{1-[(5′-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}-3-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (820 mg).

Workup

  1. washwashed sequentially with water and saturated sodium chloride solution
  2. dry with materialdried over anhydrous sodium sulfate
  3. concentrationconcentrated under reduced pressure
  4. customThe resulting residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-95ef784e0c7444bdb9fd29b3fc1a4f33
Source dataset
uspto-grants-2014_05
Patent number
US08729095B2

Reaction notes

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