Thionyl Chloride → N-(3-chloro-4-(3-chlorobenzyloxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine

HRID 511783Notes

Reaction equation

HRID 511783 reaction equation
[F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[NH2:21]>CN(C=O)C.CC(N(C)C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1

Participants

6

Reactant 3

HCID 24386Thionyl ChlorideHCID 283738183-Chloro-4-(3-chlorobenzyloxy)anilineHCID 66823511HCID 66823511, compound

Product 1

HCID 68159039N-(3-chloro-4-(3-chlorobenzyloxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 31374DimethylacetamideSolvent

Procedure

A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.0 g, 6.06 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 40 min to give a homogeneous mixture. It was evaporated under reduced pressure at 40° C. (bath temperature) to give a light brown solid. To this solid was added a mixture of 3-chloro-4-(3-chlorobenzyloxy)aniline (1.79 g, 6.67 mmol) and dry DMA (10 mL). The residue of 3-chloro-4-(3-chlorobenzyloxy)aniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 1 h 30 min. It was partitioned in between ethyl acetate (400 mL) and water (400 mL). The ethyl acetate layer was separated and washed further with water (2×200 mL), dried (MgSO4) and evaporated to give a crude product of N-(3-chloro-4-(3-chlorobenzyloxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (201). Chromatography on silica gel (dichloromethane/MeOH=25:1) gave pure 201 (2.52 g, 100%) as a yellow/orange solid, mp 196-198° C.; 1H NMR δ [(CD3)2SO] 10.03 (s, 1H), 8.94 (s, 1H), 8.69 (s, 1H), 8.21 (s, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.75 (dd, J=9.0, 2.5 Hz, 1H), 7.57-7.54 (m, 1H), 7.49-7.39 (m, 3H), 7.31 (d, J=9.0 Hz, 1H). Anal. Calcd for C20H13Cl2FN4O: C, 57.85; H, 3.16; N, 13.49. Found C, 57.60; H, 3.45; N, 13.32.

Workup

  1. temperatureunder reflux for 40 min
  2. customto give a homogeneous mixture
  3. customIt was evaporated under reduced pressure at 40° C. (bath temperature)
  4. customto give a light brown solid
  5. additionTo this solid was added
  6. washThe residue of 3-chloro-4-(3-chlorobenzyloxy)aniline was washed down with more DMA (2×2 mL)
  7. customIt was partitioned in between ethyl acetate (400 mL) and water (400 mL)
  8. customThe ethyl acetate layer was separated
  9. washwashed further with water (2×200 mL)
  10. dry with materialdried (MgSO4)
  11. customevaporated

Sources & evidence

ORD record
ord-f972d3db920f4bd091b032342f73b702
Source dataset
uspto-grants-2015_08
Patent number
US09101632B2

Reaction notes

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