Diisopropylethylamine → N4-(4-ethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine

HRID 71570

Reaction equation

HRID 71570 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:28]1[CH2:38][O:37][C:36]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=2[O:29]1>C(O)CO>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:33][C:32]3[CH:34]=[CH:35][C:36]4[O:37][CH2:38][CH2:28][O:29][C:30]=4[CH:31]=3)[N:7]=2)=[CH:10][CH:11]=1)[CH3:17]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 891481,4-Benzodioxan-6-ylamineHCID 220606042-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine

Product 1

HCID 22060247N4-(4-ethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamineYield 60%

Reagents, catalysts & solvents 1

HCID 174Ethylene GlycolSolvent

Conditions

Temperature
200 °C

Procedure

To a solution of 2-chloro-N4-(4-ethyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.93 mmol) in ethylene glycol (3 mL) under nitrogen at room temperature was added i-Pr2EtN, 0.93 mmol) followed by 3,4-ethylenedioxyaniline (0.17 g, 1.12 mmol). The reaction mixture was heated to 200° C. for 5 h and then cooled to room temperature. The mixture was partitioned between H2O (20 mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude brown solid was purified by chromatography (2:1 CHCl3/EtOAc) to afford N4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (0.21 g, 60%) as a tan solid: Rf 0.42 (4:1 CHCl3/EtOAc); mp 163.8-167.2° C. (DSC); 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=2.8 Hz, 1H), 7.50-7.45 (m, 2H), 7.17 (d, J=2.5 Hz, 1H), 6.92-6.86 (m, 3H), 6.80-6.75 (m, 2H), 6.64 (bs, 1H), 4.26-4.21 (m, 4H), 4.03 (q, J=7.0, 2H), 1.42 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.1, 150.6, 143.6, 142.8, 140.3, 140.0, 139.5, 139.3, 134.0, 130.8, 123.2, 117.2, 115.1, 113.6, 109.4, 64.6, 64.0, 15.1; IR (ATR) 3403 cm−1; ESI MS m/z 383 [C20H19FN4O3+H]+; HPLC (Method A) 98.1% (AUC), tR=12.0 min. Anal. Calcd for C20H19FN4O3: C, 62.82; H, 5.01; N, 14.65. Found: C, 62.06; H, 5.01; N, 14.35.

Workup

  1. temperaturecooled to room temperature
  2. customThe mixture was partitioned between H2O (20 mL) and EtOAc (20 mL)
  3. extractionthe aqueous layer was extracted with EtOAc (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 (2:1 CHCl3/EtOAc)

Sources & evidence

ORD record
ord-5844650e725c48f4bd49cf13b7c1edbf
Source dataset
uspto-grants-2014_09
Patent number
US08822685B2

Linked notes

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