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

HRID 511815Notes

Reaction equation

HRID 511815 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[Cl: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[Cl:26])#[CH:18]

Participants

6

Reactant 3

HCID 24386Thionyl ChlorideHCID 668235116-Fluoropyrido[3,4-d]pyrimidinoneHCID 866689474-Chloro-3-ethynylaniline

Product 1

HCID 86668946N-(3-ethynyl-4-chlorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amineYield 100.4%

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 24 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-chloroaniline (J. Org. Chem., 1981, 46, 2280-2286) (1.67 g, 11.0 mmol) and dry DMA (15 mL). The residue of 3-ethynyl-4-chloroaniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 24 h. It was poured into water (300 mL) and the residue washed down with MeOH. 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 (5×25 mL); ethyl acetate/petroleum ether (1:10) (4×25 mL) and dried to give N-(3-ethynyl-4-chlorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (209) (3.0 g, 100%) as a pale brown solid, mp 218-222° C.; 1H NMR δ [(CD3)2SO] 10.13 (s, 1H), 8.98 (s, 1H), 8.77 (s, 1H), 8.32-8.22 (m, 2H), 7.95 (dd, J=8.8, 2.6 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 4.60 (s, 1H). Anal. Calcd for C15H8ClFN4.0.5H2O.0.5MeOH: C, 57.51; H, 3.43; N, 17.31. Found C, 57.33; H, 3.13; N, 17.10.

Workup

  1. temperatureunder reflux for 24 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-chloroaniline was washed down with more DMA (2×2 mL)
  6. additionIt was poured into water (300 mL)
  7. washthe residue washed down with MeOH
  8. customat room temperature
  9. additionPetroleum ether (300 mL) was added
  10. stirringstirred at room temperature for 30 min
  11. customThe petroleum ether layer was decanted
  12. filtrationThe solid was collected by filtration
  13. washwashed with water (5×25 mL)
  14. dry with materialethyl acetate/petroleum ether (1:10) (4×25 mL) and dried

Sources & evidence

ORD record
ord-b54e46ffea954a4c935b8746045e3119
Source dataset
uspto-grants-2015_08
Patent number
US09101632B2

Reaction notes

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