Toluene → 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

HRID 1038668Notes

Reaction equation

HRID 1038668 reaction equation
[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[NH2:4].C(Cl)(Cl)=O.C1(C)C=CC=CC=1.ClC1C(OC)=CC=C(Cl)C=1N[C:36](=[O:59])[N:37]([CH3:58])[C:38]1[CH:43]=[C:42]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]3)=[CH:47][CH:46]=2)[N:41]=[CH:40][N:39]=1>O1CCOCC1>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[NH:4][C:36](=[O:59])[N:37]([CH3:58])[C:38]1[CH:43]=[C:42]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([N:51]3[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]3)=[CH:49][CH:50]=2)[N:41]=[CH:40][N:39]=1

Participants

6

Reactant 4

HCID 1140TolueneHCID 6371PhosgeneHCID 56594745HCID 56594745, compoundHCID 594862532,6-Dichloro-3,5-dimethoxyaniline

Product 1

HCID 577103253-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-methyl-1-{6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-urea

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

To a solution of 2,6-dichloro-3,5-dimethoxyaniline (preparation 2, 74 mg, 0.34 mmol, 1.25 eq.) in dioxane is added 20% phosgene solution in toluene (191 μl, 0.36 mmol, 1.35 eq.) under argon. The reaction mixture is stirred for further 6 h at room temperature under argon. Then, the solvent is evaporated and the colorless crystalline residue is taken up in dry toluene (2.5 ml). After the addition of N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (see example 1, 80 mg, 0.27 mmol, 1.0 eq.) the suspension is stirred at 70° C. for 36 h under argon. After cooling the precipitate is filtered off, washed with toluene, methanol/ether 1:1, and ether to give a beige powder. The crude product is purified by flash chromatography (1% MeOH in DCM to 16% MeOH in DCM within 30 min). The fractions containing the product are pooled, evaporated, and triturated with ether. The precipitate is filtered off, washed (1× cold methanol/ether 1:1, 1× ether), and vacuum dried at 45° C. over night to afford the title compound as colorless powder: m.p. 221° C. (dec.), ESI-MS: 546.1/548.0/550.0 [MH]+.

Workup

  1. customThen, the solvent is evaporated
  2. stirringis stirred at 70° C. for 36 h under argon
  3. temperatureAfter cooling the precipitate
  4. filtrationis filtered off
  5. washwashed with toluene, methanol/ether 1:1, and ether
  6. customto give a beige powder
  7. customThe crude product is purified by flash chromatography (1% MeOH in DCM to 16% MeOH in DCM within 30 min)
  8. additionThe fractions containing the product
  9. customevaporated
  10. customtriturated with ether
  11. filtrationThe precipitate is filtered off
  12. washwashed (1× cold methanol/ether 1:1, 1× ether), and vacuum
  13. customdried at 45° C. over night

Sources & evidence

ORD record
ord-4a0afe69af9941aaa7292271dbedf869
Source dataset
uspto-grants-2013_10
Patent number
US08552002B2

Reaction notes

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