Thionyl Chloride → N-(3-ethynyl-4-fluorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine

HRID 511812Notes

Reaction equation

HRID 511812 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.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22])#[CH:18]>CN(C=O)C.CC(N(C)C)=O>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][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:23]=[CH:24][C:25]=1[F:26])#[CH:18]

Participants

6

Reactant 3

HCID 24386Thionyl ChlorideHCID 126873623-Ethynyl-4-fluoroanilineHCID 668235116-Fluoropyrido[3,4-d]pyrimidinone

Product 1

HCID 86668943N-(3-ethynyl-4-fluorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amineYield 85%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 31374DimethylacetamideSolvent

Procedure

A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 1 h to give a homogeneous mixture. It was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-ethynyl-4-fluoroaniline (J. Org. Chem., 1981, 46, 2280-2286) (1.49 g, 11.0 mmol) and dry DMA (15 mL). The residue of 3-ethynyl-4-fluoroaniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 45 h. It was poured into water (300 mL). The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by filtration and washed with water (5×50 mL); ethyl acetate/petroleum ether (1:10) (4×50 mL) and dried to give N-(3-ethynyl-4-fluorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (208) (2.39 g, 85%) as a pale brown solid, mp 223-226° C.; 1H NMR δ [(CD3)2SO] 10.10 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.24 (br s, 1H),), 8.12 (dd, J=6.4, 2.8 Hz, 1H), 7.96-7.88 (m, 1H), 7.39 (t, J=9.1 Hz, 1H), 4.54 (s, 1H). Anal. Calcd for C15H8F2N4.1.8H2O: C, 57.25; H, 3.72; N, 17.80. Found C, 57.27; H, 3.49; N, 17.90.

Workup

  1. temperatureunder reflux for 1 h
  2. customto give a homogeneous mixture
  3. customIt was evaporated under reduced pressure at 45° C. (bath temperature)
  4. customto give a light brown solid
  5. washThe residue of 3-ethynyl-4-fluoroaniline was washed down with more DMA (2×2 mL)
  6. additionIt was poured into water (300 mL)
  7. customat room temperature
  8. additionPetroleum ether (300 mL) was added
  9. stirringstirred at room temperature for 30 min
  10. customThe petroleum ether layer was decanted
  11. filtrationThe solid was collected by filtration
  12. washwashed with water (5×50 mL)
  13. dry with materialethyl acetate/petroleum ether (1:10) (4×50 mL) and dried

Sources & evidence

ORD record
ord-4c92f6b67638475b82698f2ec24844a7
Source dataset
uspto-grants-2015_08
Patent number
US09101632B2

Reaction notes

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