N,N-Dimethylaniline → HCID 86682420, compound

HRID 1777721Notes

Reaction equation

HRID 1777721 reaction equation
O=P(Cl)(Cl)Cl.CN(C)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:38]=[C:37]3[C:32]([CH:33]=[CH:34][CH:35]=[N:36]3)=[C:31]([Cl:39])[N:30]=2)=[C:25]([Cl:40])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:41]([O-])([O-])=O.[Na+].[Na+]>>[CH2:15]([N:22]([CH2:41][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:38]=[C:37]3[C:32]([CH:33]=[CH:34][CH:35]=[N:36]3)=[C:31]([Cl:39])[N:30]=2)=[C:25]([Cl:40])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1

Participants

5

Reactant 4

HCID 949N,N-DimethylanilineHCID 10340Sodium CarbonateHCID 24813Phosphorus oxychlorideHCID 86682421HCID 86682421, compound

Product 1

HCID 86682420HCID 86682420, compound

Procedure

To a suspension of 2-methylnicotinic acid, 1 (274 mg, 2.0 mmol, 1 eq) in freshly distilled THF (5 mL) was added at −78° C. a solution of LDA (2.5 mL, 5.0 mmol, 2.5 eq) under Ar(g). The resulting purple solution was stirred at −78° C. for 30 min, and then warmed up to 0° C. for 1.5 h. The mixture was then cooled down to −78° C., and a solution of 2-chloro-4-dibenzylamino-benzonitrile, 2 (800 mg, 2.4 mmol, 1.2 eq) in THF (5 mL) was added. The reaction mixture was left to warm up to rt overnight, and was then quenched at 0° C. with H2O (20 mL), and extracted with CHCl3 (3×10 mL) and EtOAc (2×10 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo to give a crude pale red oil (1.15 g). To a solution of this residue in POCl3 (4.0 mL, 44 mmol, 22 eq) was added dimethylaniline (51 μL, 0.4 mmol, 0.20 eq). The mixture was refluxed at 100° C. under Ar(g) overnight; once cooled down, the solution was poured very slowly into a saturated Na2CO3 solution (50 mL) at 0° C., and was then partitioned and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (3:1-0:1) to yield an inseparable mixture of the product, 3, and the by-product benzyl-[3-chloro-4-(5-chloro-[1,6]naphthyridin-7-yl)-phenyl]-amine as a pale yellow oil (183 mg, 1:1 ratio; 3=10%, by-product=12% over 2 steps)

Workup

  1. temperatureonce cooled down
  2. customwas then partitioned
  3. extractionextracted with CH2Cl2 (3×20 mL)
  4. dry with materialThe combined organic extracts were dried over MgSO4
  5. customthe solvent was removed in vacuo
  6. customThe residue was further purified by silica gel column chromatography with hexane/EtOAc (3:1-0:1)
  7. customto yield
  8. additionan inseparable mixture of the product, 3

Sources & evidence

ORD record
ord-2b51e6b1b6af441788cf3a2dff782ef9
Source dataset
uspto-grants-2016_02
Patent number
US09266879B2

Reaction notes

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