4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylaniline
Benzenamine, 4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)-
CAS: 694499-26-8
Molecular Formula: C13H18F3N3
4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylaniline - Names and Identifiers
4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylaniline - Physico-chemical Properties
| Molecular Formula | C13H18F3N3 |
| Molar Mass | 273.3 |
| Density | 1.227 |
| Boling Point | 329.1±42.0 °C(Predicted) |
| pKa | 7.55±0.10(Predicted) |
| Storage Condition | under inert gas (nitrogen or Argon) at 2–8 °C |
| Use | This product is for scientific research only and shall not be used for other purposes. |
4-(4-Methylpiperazin-1-ylmethyl)-3-trifluoromethylaniline - Reference Information
| overview | with the development and application of tyrosine kinase inhibitors (TKIs), the clinical outcomes of patients with chronic myeloid leukemia (CML) and urban chromosome positive acute lymphoblastic leukemia (Ph + ALL) are significantly improved compared with before. Imatinib mesylate is the world's first approved first-generation TKIs, which can specifically block the binding position of adenosine triphosphate (ATP) on ABL kinase, so that tyrosine residues cannot be phosphorylated, thereby inhibiting BCR-ABL protein activity, leading to BCR-ABL-positive cell proliferation inhibition and increased apoptosis. This molecular targeted therapy for pathogenesis has greatly changed the prognosis of patients with CML and Ph + ALL. However, nearly 35% of CML patients who received imatinib did not achieve complete cytogenetic remission (CCyR), which may be the main reason for recurrence in these patients. Second-generation TKIs (such as dasatinib and nilotinib) can improve the efficacy and overall survival of patients who have failed imatinib treatment. Currently, dasatinib and nilotinib have been approved as first-line treatment for patients with chronic CML. |
| Mechanism of action | Punatinib (pratinib) is an oral multi-target TKIs compound is an pan-BCR-ABL inhibitor. The semi-inhibitory concentrations (IC50) of ABL and T315I mutant ABL tyrosine kinase activity in vitro are 0.4 and 2.0nmol • L-1, respectively, and the IC50 value is L-1 0.1~20nmol •, which also inhibits the activity of other oncogenic kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), erythropoietin human hepatocyte (Eph) receptor, cytoplasmic tyrosine kinase Src family (SFK), tyrosine kinase membrane receptor gene (C-kit), orphan receptor tyrosine kinase (RET), angiopoietin type I tyrosine kinase receptor 2(TIE2) and FMS-like tyrosine kinase 3(FLT3). The molecular structure of pratinib (pratinib) is designed according to different ways of interacting with T315I, independent of the existing kinase inhibitor structure. ABL inhibitors include aspartate-phenylalanine-glycine (DFG-in, class 1 inhibitor) and aspartate-phenylalanine-glycine (DFG-out, class 2 inhibitor), depending on how they interact with BCR-ABL. Class 1 inhibitors are the first generation of small molecule kinase inhibitors, which target the ATP binding site of the enzyme activating group, and are characterized by the open configuration of the activation ring; Class 2 inhibitors bind to other hydrophobic sites and are different from Class 1 inhibitors to form configuration inactivation. In contrast, class 2 inhibitors have higher selectivity and efficacy than class 1. Class 1 inhibitors include sunitinib, dasatinib, and class 2 inhibitors include imatinib, nilotinib, and pratinib (pratinib). Regardless of the combination method, imatinib, dasatinib, and nilotinib will form a key hydrogen bond with the side chain of the gated gene residue Thr315 of wild-type ABL, which also contains some lipophilicity, and is located near Thr315. The hydrophobic bag combines. But this hydrogen bond is easily damaged, and the mutation of the gated gene residue into isoleucine also causes steric hindrance, which restricts the inhibitor from binding to the adjacent Thr315 hydrophobic bag. Thus, imatinib, dasatinib, and nilotinib did not inhibit ABL kinase activity of the Thr315 point mutation. T315I mutation was clinically observed in 15%-20% patients, and this highly resistant mutation occurred in the gated gene region of the ATP binding site of the BCR-ABL fusion protein ABL kinase. It is worth noting that pratinib (pratinib) can avoid the side chain binding with wild-type BCRABLT315I, forming a Van der Waals gravity that is conducive to binding to the T315I mutant side chain isoleucine. In addition, pratinib (pratinib) can also regulate the steric hindrance of isoleucine mutants, combining with T315I point mutation to inhibit ABL kinase activity. |
| preparation | 1) preparation of 3-bromoimidazolo [1,2-b] pyridazine (3) dissolving 200g(1.68mol) imidazolo [1,2-b] pyridazine (2) in 2L chloroform, 328.8g(1.85mol)N-bromosuccinimide was added and heated and refluxed (61 ℃) overnight. TLC showed complete reaction. The organic phase was washed with water (1L × 2), saturated sodium chloride solution was washed (1L × 1), anhydrous sodium sulfate was dried, and 321g light yellow solid 3 was obtained by spinning dry solvent, with a yield of 96.7%,mp145~147 ℃ (literature: mp146 ~ 147 ℃). MSm/z:197.9[M + H]+. 2) Preparation of 4-Methyl -3-Trimethylsilyl acetynyl benzoate (5) Add 3-iodine -4-methyl benzoate (4)300g(1.09mol), 2.06g (11mmol) iodide, 7.63g (11mmol) bis (triphenylphosphine) palladium dichloride, 4L ethyl acetate, 329.3g(3.25mol) triethylamine and 159.8g(1.63mol), the gas in the argon gas replacement system is introduced, the reaction system is closed, the room temperature is stirred overnight, and the TLC detection reaction is complete. The reaction solution was filtered, the filtrate was washed with water (1L × 2) and saturated sodium chloride solution (1L × 1), anhydrous sodium sulfate was dried, and 267.4g red solid 5 was obtained by spinning the solvent. The yield was 99%, and it was directly used for the next reaction without purification. 3) Preparation of methyl 3-ethynyl-4-methylbenzoate (6) In a 5L three-neck bottle, 267.4g(1.09mol) compound 5 is added, 4L methanol is added, dissolved by mechanical stirring, 225g(1.63mol) potassium carbonate is added, the reaction process is monitored by TLC while mechanical stirring at room temperature (once every 1min), and the reaction is completed in about 5~10min. The reaction liquid was poured into 5L of water, stirred evenly, filtered and precipitated, washed once with 3L of water, and the solid was vacuum dried to obtain 180g of brown solid 6 with a yield of 95%,mp62~64 ℃. 4)3-(imidazole [1, preparation of 2-b] Methyl pyridazine -3-ethynyl)-4-methylbenzoate (7) Add 180g(1.03mol) compound 6, 198g(1.01mol) compound 3, 1.9g(10mmol) cuprous iodide, 7g(10mmol) bis (triphenylphosphine) palladium dichloride, 3LN-methylpyrrolidone (NMP), 193.4g(1.50mol) diisopropyl ethylamine (DIEA), the gas in the argon replacement system was introduced, and the gas was mechanically stirred overnight at 70 ℃, and the TLC detection reaction was complete. The reaction liquid is poured into 12L of water, stirred evenly, filtered, the obtained solid is dried, 1L of ethyl acetate is added, and stirred for 1h. Filtration, washing (200mL × 2) filter cake with ethyl acetate, vacuum drying to obtain 283g of grayish brown solid; Dissolve the solid with 4L ethyl acetate, add 38g of activated carbon, heat and reflux for 1h, filter while hot, and stand for crystallization of the filtrate to obtain 185g of light yellow crystal 7 with a yield of 63.6%,mp141~143 ℃. 5) Synthesis of Punatinib (pratinib)(1) In a 2L three-necked bottle, add 50g(0.18mol)4-((4-methylpiperazine -1-yl) methylene)-3-trifluoromethylaniline (8), 53.3g(0.18mol) compound 7,500 mL tetrahydrofuran, mechanically stirred, cooled to 0 ℃, under the condition of mechanical stirring, 123g(1.10mol) of potassium tert-butoxide dissolved in 500mL of anhydrous THF solution was slowly added dropwise. After dropwise addition, the solution was maintained at a low temperature for 10min, moved to room temperature, stirred overnight, and TLC detection reaction was complete. The reaction liquid is poured into 3L of water, stirred evenly, ethyl acetate (1L × 3) is extracted, organic phases are combined, washed with water (1L × 3), anhydrous sodium sulfate is dried, the solvent is rotated to obtain yellow solid, 100mL ethyl acetate is added to dissolve the solid, and stirred for 2 hours. Filtered, dried, and recrystallized with 1, 4-dioxane-water (volume ratio 1 ∶ 1) to obtain light yellow solid pratinib (pratinib)(1)73g, yield 71.9%,mp195~197 ℃. MSm/z:533.3[M + H]+. The purity detected by HPLC (area normalization method) was 99.65%. |
Last Update：2024-04-09 20:52:54
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