4-Butyloxyaniline → N2-(4-n-Butyloxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine

HRID 71569

Reaction equation

HRID 71569 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20](N(CC)C(C)C)(C)C.[CH2:29]([O:33][C:34]1[CH:40]=[CH:39][C:37](N)=[CH:36][CH:35]=1)[CH2:30][CH2:31][CH3:32]>C(O)CO>[CH2:29]([O:33][C:34]1[CH:40]=[CH:39][C:37]([NH:7][C:2]2[CH:20]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:36][CH:35]=1)[CH2:30][CH2:31][CH3:32]

Participants

5

Reactant 3

HCID 203524-ButyloxyanilineHCID 81531DiisopropylethylamineHCID 220603622-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine

Product 1

HCID 22060376N2-(4-n-Butyloxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamineYield 49.4%

Reagents, catalysts & solvents 1

HCID 174Ethylene GlycolSolvent

Conditions

Temperature
185 °C

Procedure

To a magnetically stirred solution of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.89 mmol) in ethylene glycol (3.0 mL) under nitrogen at room temperature was added N,N-diisopropylethylamine (0.12 g, 0.89 mmol) followed by 4-butoxyaniline (0.18 g, 1.1 mmol). The reaction mixture was heated to 185° C. for 5 h, cooled to room temperature, and partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude brown solid was purified by chromatography (silica gel, 2:1 hexanes/ethyl acetate) to afford N2-(4-n-Butyloxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine (0.18 g, 49%) as a tan solid: Rf 0.66 (silica gel, 4:1 chloroform/ethyl acetate); mp 133-135° C.; 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=3.2 Hz, 1H), 7.39 (d, J=8.9 Hz, 2H), 7.28 (d, J=2.5 Hz, 1H), 6.95 (dd, J=8.7, 2.5 Hz, 1H) 6.90-6.81 (m, 4H), 6.60 (d, J=2.4 Hz, 1H), 4.27 (s, 4H), 3.94 (t, J=6.5 Hz, 2H), 1.80-1.71 (m, 2H), 1.55-1.42 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.3, 155.1, 150.4, 143.6, 142.7, 140.3, 140.0, 139.4, 133.0, 131.7, 121.9, 117.3, 115.0, 114.7, 110.8, 68.2, 64.7, 64.5, 31.6, 19.4, 14.0; IR (ATR) 3356 cm−1; ESI MS m/z 411 [C22H23FN4O3+H]+; HPLC (Method A)>99% (AUC), tR=17.3 min. Anal. Calcd for C22H23FN4O3: C, 64.38; H, 5.65; N, 13.65. Found: C, 62.64; H, 5.59; N, 13.15.

Workup

  1. temperaturecooled to room temperature
  2. custompartitioned between water (20 mL) and ethyl acetate (20 mL)
  3. extractionThe aqueous layer was extracted with ethyl acetate (20 mL)
  4. dry with materialthe combined organic layers were dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude brown solid was purified by chromatography (silica gel, 2:1 hexanes/ethyl acetate)

Sources & evidence

ORD record
ord-ab7189789a534ce8b6bc292b022bc1f8
Source dataset
uspto-grants-2014_09
Patent number
US08822685B2

Linked notes

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