4-Fluoro-3-(trifluoromethyl)aniline → HCID 66823611, compound

HRID 1520742Notes

Reaction equation

HRID 1520742 reaction equation
[F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>O=S(Cl)Cl.C(Cl)Cl.CN(C=O)C.CC(O)C>[F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:18][C:17]3[CH:19]=[CH:20][C:14]([F:13])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)[C:4]=2[CH:3]=1

Participants

7

Reactant 2

HCID 753774-Fluoro-3-(trifluoromethyl)anilineHCID 1354173706-fluoropyrido[3,4-d]pyrimidin-4-ol

Product 1

HCID 66823611HCID 66823611, compoundYield 100%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent2×HCID 24386Thionyl ChlorideSolvent

Conditions

Temperature
84 °C

Procedure

A suspension of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (93) (4.90 g, 29.68 mmol) in SOCl2 (250 mL), CH2Cl2 (50 mL) and DMF (8 drops) was heated under reflux for 3 h. The solvents were then removed by vacuum distillation and the residue was evaporated to dryness. The resulting crude 4-chloro-6-fluoropyrido[3,4-d]pyrimidine was dissolved in CH2Cl2 (50 mL) and iPrOH (120 mL), to which 4-fluoro-3-(trifluoromethyl)aniline (5.85 g, 32.66 mmol) was added before the solution was heated under reflux at 84° C. for 30 min using an air condenser. During reflux the CH2Cl2 was evaporated and the crude product precipitated from the remaining iPrOH as a pale yellow solid. The mixture was cooled to the room temperature, poured into an ice-cold beaker of 5% aqueous Na2CO3 and stirred for 15 min at 0° C. The solid was collected by filtration, washed several times with water and then hexane before being dried in a vacuum oven (45° C.) overnight to give 6-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine (163) (9.68 g, 100%) as a yellow solid, m.p. 247-249° C. 1H NMR [(CD3)2SO] δ 10.25 (s, 1H), 8.99 (s, 1H), 8.75 (s, 1H), 8.34 (dd, J=6.5, 2.7 Hz, 1H), 8.26-8.30 (m, 1H), 8.24 (s, 1H), 7.60 (t, J=9.7 Hz, 1H). Anal. Calcd for C14H7F5N4: C, 51.54; H, 2.16; N, 17.17%. found: C, 51.37; H, 2.30; N, 16.93%.

Workup

  1. temperaturewas heated
  2. temperatureunder reflux for 3 h
  3. customThe solvents were then removed by vacuum distillation
  4. customthe residue was evaporated to dryness
  5. dissolutionThe resulting crude 4-chloro-6-fluoropyrido[3,4-d]pyrimidine was dissolved in CH2Cl2 (50 mL)
  6. temperaturewas heated
  7. customwas evaporated
  8. customthe crude product precipitated from the remaining iPrOH as a pale yellow solid
  9. temperatureThe mixture was cooled to the room temperature
  10. additionpoured into an ice-cold beaker of 5% aqueous Na2CO3
  11. filtrationThe solid was collected by filtration
  12. washwashed several times with water
  13. dry with materialhexane before being dried in a vacuum oven (45° C.) overnight

Sources & evidence

ORD record
ord-a1f1262fa2364e6c936b31d3fa8e5490
Source dataset
uspto-grants-2015_07
Patent number
US09073916B2

Reaction notes

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