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Chemical Structure| 943319-70-8
Chemical Structure| 943319-70-8
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Product Details of [ 943319-70-8 ]

CAS No. :943319-70-8 MDL No. :MFCD17215203
Formula : C29H27F3N6O Boiling Point : -
Linear Structure Formula :- InChI Key :PHXJVRSECIGDHY-UHFFFAOYSA-N
M.W : 532.56 Pubchem ID :24826799
Synonyms :
AP24534
Chemical Name :3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

Safety of [ 943319-70-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H320-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 943319-70-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 943319-70-8 ]

[ 943319-70-8 ] Synthesis Path-Downstream   1~40

YieldReaction ConditionsOperation in experiment
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 72h; Inert atmosphere; 16 (R)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide General procedure: (imidazo[1,2-bJpyridazin-3-ylethynyl)-4-methylbenzamide: A mixture of 3-ethynyl imidazo[ I ,2- b]pyridazine (0.051 g, 0.34 mmol), 0.150 g (0.28 mmol) of (R)-N-(4-((3-(dimethylamino)pyrrol idin- 1 -yl)methyl)-3-(trifluoromethyl)phenyl)-3 -iodo-4-methylbenzamide, 0.016 g (0.014 mmol) of Pd(PPh3)4, 0.004 g (0.021 mmol) of Cul, and 0.09 mL (0.51 mmol) of N,N-diisopropylethylarnine in 3.5 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 3 days (reaction pushed to completion with additional equivalents ofreagents and heating to 80 °C). The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (eluted with 0-10% MeOH/DCM; MeOR was presaturated with ammonia gas) to provide 0.020 g of product as a solid: 547 m/z (M+H).
  • 2
  • [ 943320-50-1 ]
  • [ 943320-61-4 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;
With diisopropylamine; copper(l) chloride In acetonitrile for 10h; Irradiation; 2.3-3.3 3) Compound D and compound E were subjected to the acetonitrile solvent containing CuCl and diisopropylamine, and the blue LED light source were illuminated for 10h to generate the target product panatinib; Wherein, compound D was 1mmol, compound E was 1.1mmol, CuCl concentration was 0.03mmol, acridine salt was 0.01mmol, diisopropylamine was 1.2mmol. The volume of acetonitrile solvent was 2 mL. The product compound D in the above step (2) and the panatinib product in the step (3) were subjected to nuclear magnetic measurement, and the measurement results are as follows:
  • 3
  • [ 694499-24-6 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 10% Pd/C; hydrogen / ethyl acetate / 4 h 2: potassium <i>tert</i>-butylate / 2-methyltetrahydrofuran / 3 h / 13 - 23 °C
  • 4
  • [ 694499-26-8 ]
  • C17H13N3O2*ClH [ No CAS ]
  • ponatinib [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium tert-butylate; In 2-methyltetrahydrofuran; at 13 - 23℃; for 3h; Unit Operation 3. 1: Drying Reaction Mixture AP25047, AP24592, and 2-methyl tetrahydrofuran (2-Me-THF) are charged to a reactor. The mixture is concentrated at reduced pressure to a target volume. Additional 2-methyl tetrahdyrofuran is added and the distillation repeated. Following another charge of 2-methyl tetrahydrofuran and a distillation cycle, the water content of the mixture is determined in IPC- 1 (KF). If the IPC-1 criterion is met, the process is continued to Unit Operation 3.2. Unit Operation 3.2: Reaction The suspension is maintained with stirring at a target temperature of 13 - 23C range while potassium fe -butoxide (KOfBu) is charged. After a period of not less than 3 hours, the reaction progress is determined by HPLC (IPC-2). If the IPC criterion is met, the process is continued to Unit Operation 3.3. Unit Operation 3.3: Quench and Extractions The reaction mixture is diluted with 2-methyltetrahydrofuran (2-Me-THF), and quenched by the addition of aqueous sodium chloride solution. The organic layer is separated and the aqueous layer is extracted twice with 2-methyl tetrahydrofuran. The combined organic layers are sequentially washed with aqueous sodium chloride and water. The organic layer is then aged at 15 - 30C. Unit Operation 3.4: Concentration / Solvent Exchange After aging (see Unit Operation 3.3), the mixture is passed through a cartridge filter and concentrated under vacuum to a target volume. 1 -Propanol is charged and allowed to stir at elevated temperature to furnish a solution, which is distilled under vacuum to a target volume and then cooled slowly to a temperature range of 20 - 30C. Unit Operation 3.5: Crystallization The product solution in 1 -propanol is aged with stirring at a temperature of 20 - 30C until the presence of solids is visually observed. Acetonitrile is charged to the suspension with stirring and the resulting suspension is aged for an additional 60 - 120 minutes at 20 - 30C with agitation prior to isolation in the next Unit Operation. Unit Operation 3.6: Isolation / Drying The slurry generated in Unit Operation 3.5 is isolated under vacuum in a filter/dryer. The solids are washed twice with a mixture of 1-propanol and acetonitrile. The solids are then dried under vacuum and monitored by IPC-3 (LOD, gravimetric). If the IPC criterion is met, the product is discharged as an off-white to yellow solid and packaged in double polyethylene bags for storage at ambient temperatures.
  • 5
  • [ 943319-70-8 ]
  • [ 1114544-31-8 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In ethanol at 60 - 70℃; 4 Step 4 - Synthesis of Ponatinib HCI Unit Operation 4. 1: Dissolution AP24534 free base and absolute ethanol (EtOH) are charged to a reactor and stirred at 60 - 75°C to generate a solution. Dissolution is verified by visual observation. Unit Operation 4.2: Clarification The solution is passed through a filter, which is then washed with ethanol at 60-78°C. Unit Operation 4.3: Acidification / Seeding The product solution is concentrated under vacuum to a target volume. With stirring, an initial portion (approximately 25%) of a solution of 1 N hydrogen chloride in ethanol is then charged to the reactor. The solution is treated with qualified seed crystals of AP24534 HCI at a temperature of 60-70°C to initiate crystallization. The process is continued to Unit Operation 4.4. Unit Operation 4.4: Crystallization Once the presence of solids in the reactor is verified by visual observation, the remainder (approximately 75%) of the 1 N hydrogen chloride solution in ethanol is slowly added to the stirred mixture. The mixture is aged for at least 10 minutes and IPC-1 is performed to determine the pH of the solution. If the IPC criterion is met, the mixture is cooled to a temperature of 5-15°C and aged with stirring. Unit Operation 4.5: Isolation / Drying The solid product is isolated by filtration and washed with ethanol at a temperature of 5- 15°C. Excess ethanol is removed from the solid product by slow agitation and nitrogen flow at ambient temperature. The solid is then dried under vacuum at 60-70°C. The drying is monitored by IPC-2 (LOD, gravimetric). If the IPC-2 criterion is met, ponatinib HCI is discharged as an off-white to yellow solid and packaged in double polyethylene bags for storage in plastic drums at 20 - 30°C.
With hydrogenchloride In ethanol; acetonitrile at 50℃; for 1h; 1 Example 1: Preparation of Ponatinib hydrochloride (in EtOH/MeCN) Example 1: Preparation of Ponatinib hydrochloride (in EtOH/MeCN) To a suspension of Ponatinib free base (4 g) in MeCN (20 ml) HCl in EtOH (10 ml) was added at 50°C. The mixture was stirred at this temperature for lh and then allowed to reach room temperature over 3h. The resulted solid was collected by filtration and dried under reduced pressure at 40°C over 48h. Ponatinib hydrochloride form 1 was obtained as a solid (1.2g, 28% yield). According to H NMR the product contains ca. 0.6% of ethanol. A crystal form showing some characteristic peaks which were not too well defined was found. DSC analysis showed multiple small endotherms with an onset of peaks at ca. 77.8°C, 113.7°C and 166.7°C; a possible exotherm with peak at ca. 221.9°C and a final endotherm with onset of ca. 246.6°C. The corresponding XRD is shown in figure 3 top and was indicative of a sample comprising a significant amount of amorphous material.
With hydrogenchloride In methanol at 0 - 5℃; 9 Example 9 3-(Imidazo[ 1 ,2-bj pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- 1 -yl)methyl)-3 -(trifluoromethyl)phenyl)benzamide hydrochloride 3-(Imidazo [1 ,2-bj pyridazin-3 -ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- 1 -yl)methyl)-3- (trifluoromethyl)phenyl)benzamide (1 mmol) was dissolved in methanol (5 vol.) and saturated with HC1 gas at 0-5°C and stirred for 1-2 hrs. The solid was filtered, washed with methanol, suction dried and dried at 50-60°C to obtain hydrochloride salt.
0.87 g With hydrogenchloride In ethanol; acetonitrile at 25 - 45℃; for 2.5h; 2 preparation of α crystalline form of the salt 3-(imidazo[1,2-b] pyridazin-3-ylethynyl)-4-methyl-N-(4 - ((4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)benzamide hydrochloride At room temperature (about 24 °C), 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4 -((4-methylpiperazin-1-yl)-3- (trifluoromethyl)phenyl)benzamide (1.00 g) was added to CH3CN (20 mL). The mixture was heated to 45 ° C and the mixture was stirred at 45 ° C for 1 h. Hydrochloric acid (36 wt%, 207.8 mg) was added dropwise to the mixture in absolute ethanol (2 mL). to obtain an orange solution, After the mixture was stirred at 45 °C for 30 min, The mixture was cooled to 25 °C, The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered to obtain a white solid, and the white solid was dried at 50 °C for 24 h to give 0.87 g of an off-white solid. The resulting solid X-ray diffractometer was used, The diffraction pattern is basically as shown in Fig.3.
With hydrogenchloride In water; acetone at 15 - 30℃;

  • 6
  • [ 18087-73-5 ]
  • ponatinib [ No CAS ]
  • 7
  • [ 90347-66-3 ]
  • ponatinib [ No CAS ]
  • 8
  • [ 1001203-03-7 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 4 h / 5 - 10 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C 3: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; tricyclohexylphosphine; caesium carbonate / N,N-dimethyl-formamide / 8 h / 80 °C / Inert atmosphere
  • 9
  • [ 957147-18-1 ]
  • [ 18087-73-5 ]
  • ponatinib [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; caesium carbonate; tricyclohexylphosphine; In N,N-dimethyl-formamide; at 80℃; for 8h;Inert atmosphere; To a 30 ml tube was added 3-ethynyl-4-methyl-N- [4- (4-methylpiperazin-1-ylmethyl) -3-trifluoromethylPhenyl] benzamide (126 mg, 0.3 mm & lt; 1 & gt;), 3 & lt; / RTI & gt; bromomethine [1,2_b] U daxazine (59 mg, 0.3 mmo 1), Pd (PPh3)(1 mg, 0.015 mmol), CuI (6 mg, 0.03 mmol), PCy3 (8 mg, 0.015 mmol), Cs2C0 (99 mg, 0.3 mmol)DMFlOml, replaced with argon for 5 minutes and then stirred at 80 C for 8 hours. With ethyl acetate (15 ml x 4), saturated with NaClSolution (30 ml). The organic layers were combined and dried over anhydrous Na2S04. The organic solution was concentrated under reduced pressure and the residue was passed throughThe title compound was obtained in a yield of 79%.
  • 10
  • [ 52107-98-9 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 0 - 30 °C 2.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / Inert atmosphere 2.2: 20 °C / Inert atmosphere 3.1: thionyl chloride / dichloromethane 4.1: dichloromethane
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 1.5 h / 0 - 20 °C 2.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / Inert atmosphere 2.2: 20 °C / Inert atmosphere 3.1: sodium hydroxide / tetrahydrofuran / 20 °C 4.1: thionyl chloride / dichloromethane 5.1: dichloromethane
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 1.5 h / 15 - 25 °C 2.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / Inert atmosphere 2.2: 20 °C / Inert atmosphere 3.1: ethanol / 0 - 20 °C 4.1: thionyl chloride / dichloromethane 5.1: dichloromethane
Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran / 4 h / 20 °C 2: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / toluene / 24 h / 58 °C / Inert atmosphere 3: potassium carbonate / methanol / 3 h / 20 °C / Inert atmosphere 4: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; tricyclohexylphosphine; caesium carbonate / N,N-dimethyl-formamide / 8 h / 80 °C / Inert atmosphere

  • 11
  • [ 766-55-2 ]
  • ponatinib [ No CAS ]
  • 12
  • [ 876322-73-5 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 1.5 h / 15 - 25 °C 2.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / Inert atmosphere 2.2: 20 °C / Inert atmosphere 3.1: ethanol / 0 - 20 °C 4.1: thionyl chloride / dichloromethane 5.1: dichloromethane
  • 13
  • [ 943319-70-8 ]
  • [ 1795740-48-5 ]
YieldReaction ConditionsOperation in experiment
62% With hydrogen bromide In isopropyl alcohol at 20 - 50℃; 1 Example 1 100 mg (0.188 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide was dissolved in 3 mL of 2-propanol by heating to 50°C. 22 μ (0.189 mmol) of hydrobromic acid (48% solution) was diluted with 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C. The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition until constant weight is reached. Yield: 71.2 mg (62%) FTIR spectrum confirmed the structure.
  • 14
  • [ 943319-70-8 ]
  • [ 1795130-62-9 ]
YieldReaction ConditionsOperation in experiment
48% With phosphoric acid In methanol at 20 - 50℃; 4 Example 4 Preparation of salt of ponatinib and phosphoric acid Example 4 Preparation of salt of ponatinib and phosphoric acid 100 mg (0.188 mmol) of ponatinib was dissolved in 15 mL of methanol by heating to 50°C. 13 μ (0.190 mmol) of phosphoric acid (85% solution) was diluted with 0.5 mL of methanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C. The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition. Yield: 57 mg (48%) 31P-NMR analysis confirmed the presence of phosphoric acid.
  • 15
  • [ 943319-70-8 ]
  • [ 2364346-96-1 ]
YieldReaction ConditionsOperation in experiment
32% With sulfuric acid In methanol at 20 - 50℃; 5 Example 5 Preparation of salt of ponatinib and sulphuric acid Example 5 Preparation of salt of ponatinib and sulphuric acid 100 mg (0.188 mmol) of ponatinib was dissolved in 15 mL of methanol by heating to 50°C. 10.5 μΙ (0.190 mmol) of sulphuric acid (96% solution) was diluted with 0.5 mL of methanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C. The solution at 40°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition. Yield: 38 mg (32%)
  • 16
  • [ 943319-70-8 ]
  • [ 65-85-0 ]
  • [ 1795130-52-7 ]
YieldReaction ConditionsOperation in experiment
63% In isopropyl alcohol at 20 - 50℃; 1 Example 1 Preparation of salt of ponatinib and benzoic acid Example 1 Preparation of salt of ponatinib and benzoic acid 100 mg (0.188 mmol) of ponatinib was dissolved in 3 mL of 2-propanol by heating to 50°C. 23 mg (0.188 mmol) of benzoic acid was dissolved in 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C. The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition. Yield: 77 mg (63%) H-NMR analysis showed a 1:1 stoichiometry of ponatinib and benzoic acid.
  • 17
  • [ 943319-70-8 ]
  • [ 77-92-9 ]
  • [ 1795130-56-1 ]
YieldReaction ConditionsOperation in experiment
41% In ethanol at 20 - 50℃; 2 Example 2 Preparation of salt of ponatinib and citric acid Example 2 Preparation of salt of ponatinib and citric acid 100 mg (0.188 mmol) of ponatinib was dissolved in 3 mL of ethanol by heating to 50°C. 36.5 mg (0.190 mmol) of citric acid was dissolved in 0.5 mL of ethanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C. The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition. Yield: 56 mg (41%) ^-NMR analysis showed a 1:1 stoichiometry of ponatinib and citric acid.
  • 18
  • [ 943319-70-8 ]
  • [ 110-17-8 ]
  • [ 1795130-58-3 ]
YieldReaction ConditionsOperation in experiment
71% In isopropyl alcohol at 20 - 50℃; 3 Example 3 Preparation of salt of ponatinib and fumaric acid Example 3 Preparation of salt of ponatinib and fumaric acid 100 mg (0.188 mmol) of ponatinib was dissolved in 15 mL of 2-propanol by heating to 50°C. 22 mg (0.189 mmol) of fumaric acid was dissolved in 0.5 mL of 2-propanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C. The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition. Yield: 86 mg (71%) ^- MR analysis showed a 2:1 stoichiometry of ponatinib and fumaric acid.
  • 19
  • [ 943319-70-8 ]
  • [ 110-15-6 ]
  • [ 1795130-65-2 ]
YieldReaction ConditionsOperation in experiment
28% In methanol at 20 - 50℃; 6 Example 6 Preparation of salt of ponatinib and succinic acid Example 6 Preparation of salt of ponatinib and succinic acid 100 mg (0.188 mmol) of ponatinib was dissolved in 3 mL of methanol by heating to 50°C. 22.5 mg (0.190 mmol) of succinic acid was dissolved in 0.5 mL of methanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C. The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition. Yield: 34 mg (28%) aH-NMR analysis showed a 1:1 stoichiometry of ponatinib and succinic acid.
  • 20
  • [ 943319-70-8 ]
  • [ 104-15-4 ]
  • [ 1795130-69-6 ]
YieldReaction ConditionsOperation in experiment
65% In methanol at 20 - 60℃; 7 Example 7 Preparation of salt of ponatinib and p-toluenesulphonic acid Example 7 Preparation of salt of ponatinib and p-toluenesulphonic acid 100 mg (0.188 mmol) of ponatinib was dissolved in 3 mL of methanol by heating to 60°C. 36 mg (0.189 mmol) of p-toluenesulphonic acid was dissolved in 0.5 mL of methanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 60°C. The solution at 60°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition. Yield: 88 mg (65%) ^- MR analysis showed a 1:1 stoichiometry of ponatinib and p-toluenesulphonic acid.
  • 21
  • [ 943319-70-8 ]
  • [ 87-69-4 ]
  • [ 1795130-72-1 ]
YieldReaction ConditionsOperation in experiment
35% In methanol at 20 - 50℃; 8 Example 8 Preparation of salt of ponatinib and L-tartaric acid Example 8 Preparation of salt of ponatinib and L-tartaric acid 100 mg (0.188 mmol) of ponatinib was dissolved in 3 mL of methanol by heating to 50°C. 28.5 mg (0.190 mmol) of L-tartaric acid was dissolved in 0.5 mL of methanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C. The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition. Yield: 45 mg (35%) ^-NMR analysis showed a 1:1 stoichiometry of ponatinib and L-tartaric acid.
  • 22
  • [ 943319-70-8 ]
  • [ 110-16-7 ]
  • [ 1795130-75-4 ]
YieldReaction ConditionsOperation in experiment
45% In methanol at 20 - 60℃; 9 Example 9 Preparation of salt of ponatinib and maleic acid Example 9 Preparation of salt of ponatinib and maleic acid 100 mg (0.188 mmol) of ponatinib was dissolved in 3 mL of methanol by heating to 50°C. 22 mg (0.190 mmol) of maleic acid was dissolved in 0.5 mL of methanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C. The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight the resulting suspension was filtered off and dried at laboratory condition. Yield: 55 mg (45%) ^- MR analysis showed a 2:1 stoichiometry of ponatinib and maleic acid.
  • 23
  • [ 943319-70-8 ]
  • [ 1114544-31-8 ]
YieldReaction ConditionsOperation in experiment
76% With hydrogenchloride In ethanol; acetonitrile at 50℃; 1 Example 1 - reproduction of the prior art (Crystal modification 1) Preparation of Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt Example 1 - reproduction of the prior art (Crystal modification 1) Preparation of Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt Process described in the patent application WO2007/075869 was reproduced. 2 g (3.755 mmol) of 3- (2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-IM-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide was suspended in 40 mL of acetonitrile and heated to 50°C with stirring. 360 pL (4.057 mmol) of hydrochloric acid was dissolved in 4 mL of ethanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C while complete dissolution occured. Within a few minutes a precipitate was formed. The suspension was cooled back to room temperature and was filtered off, washed with 6 mL of mother liqour and 6 mL of fresh acetonitrile. The solids were dried at 50°C under vacuum overnight. Yield: 1.63 g (76%) FTIR spectra confirmed the structure. The XRPD pattern was measured (Figure 1) and showed that the compound is in a crystalline state that was designated as Crystal modification 1.
  • 24
  • [ 2055390-18-4 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: sodium hydroxide / tetrahydrofuran / 20 °C 3.1: thionyl chloride / dichloromethane 4.1: dichloromethane
  • 25
  • [ 2055390-19-5 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium hydroxide / tetrahydrofuran / 20 °C 2: thionyl chloride / dichloromethane 3: dichloromethane
  • 26
  • [ 694499-22-4 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: N,N-dimethyl-formamide / 3 h / 20 °C 2.1: iron; acetic acid / 20 °C 3.1: triethylamine / dichloromethane / 1.5 h / 0 - 20 °C 4.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / Inert atmosphere 4.2: 20 °C / Inert atmosphere 5.1: sodium hydroxide / tetrahydrofuran / 20 °C 6.1: thionyl chloride / dichloromethane 7.1: dichloromethane
  • 27
  • [ 109-01-3 ]
  • [ 2055390-20-8 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane 8 Example 8 3-(Imidazo[ 1 ,2-bj pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- 1 -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide N-(4-(chloromethyl)-3 -(trifluoromethyl)phenyl)-3 -(imidazo[ 1 ,2-bjpyridazin-3 -ylethynyl)-4-methylbenzamide (1 mmol) was taken in MDC, N-methylpiperazine (1.2 mmol) was added and the mixture was stirred for about 3-4 hrs. At the completion of the reaction the reaction mass was poured into water and extracted with MDC. The organic layer was separated, dried with anhydrous sodium sulphate and evaporated to obtain solid material.
  • 28
  • [ 859027-06-8 ]
  • ponatinib [ No CAS ]
  • 29
  • [ 320-37-6 ]
  • ponatinib [ No CAS ]
  • 30
  • [ 89976-12-5 ]
  • ponatinib [ No CAS ]
  • 31
  • [ 50551-17-2 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: iron; acetic acid / 20 °C 2.1: triethylamine / dichloromethane / 1.5 h / 15 - 25 °C 3.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / Inert atmosphere 3.2: 20 °C / Inert atmosphere 4.1: ethanol / 0 - 20 °C 5.1: thionyl chloride / dichloromethane 6.1: dichloromethane
  • 32
  • [ 1638193-91-5 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: ethanol / 0 - 20 °C 3.1: thionyl chloride / dichloromethane 4.1: dichloromethane
  • 33
  • [ 1638193-92-6 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: ethanol / 0 - 20 °C 2: thionyl chloride / dichloromethane 3: dichloromethane
  • 34
  • [ 900254-46-8 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: pyridine / dichloromethane / 0 - 30 °C 2.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / Inert atmosphere 2.2: 20 °C / Inert atmosphere 3.1: thionyl chloride / dichloromethane 4.1: dichloromethane
  • 35
  • [ 82998-57-0 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 30 °C 2.1: pyridine / dichloromethane / 0 - 30 °C 3.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / Inert atmosphere 3.2: 20 °C / Inert atmosphere 4.1: thionyl chloride / dichloromethane 5.1: dichloromethane
Multi-step reaction with 6 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 30 °C 2.1: triethylamine / dichloromethane / 1.5 h / 15 - 25 °C 3.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / Inert atmosphere 3.2: 20 °C / Inert atmosphere 4.1: ethanol / 0 - 20 °C 5.1: thionyl chloride / dichloromethane 6.1: dichloromethane
Multi-step reaction with 6 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 30 °C 2.1: triethylamine / dichloromethane / 1.5 h / 0 - 20 °C 3.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / Inert atmosphere 3.2: 20 °C / Inert atmosphere 4.1: sodium hydroxide / tetrahydrofuran / 20 °C 5.1: thionyl chloride / dichloromethane 6.1: dichloromethane
Multi-step reaction with 5 steps 1: thionyl chloride / 4 h / 78 °C 2: triethylamine / tetrahydrofuran / 4 h / 20 °C 3: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / toluene / 24 h / 58 °C / Inert atmosphere 4: potassium carbonate / methanol / 3 h / 20 °C / Inert atmosphere 5: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; tricyclohexylphosphine; caesium carbonate / N,N-dimethyl-formamide / 8 h / 80 °C / Inert atmosphere

  • 36
  • [ 1488423-79-5 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: thionyl chloride / dichloromethane 3.1: dichloromethane
  • 37
  • [ 1318234-74-0 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: iron; acetic acid / 20 °C 2.1: triethylamine / dichloromethane / 1.5 h / 0 - 20 °C 3.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / Inert atmosphere 3.2: 20 °C / Inert atmosphere 4.1: sodium hydroxide / tetrahydrofuran / 20 °C 5.1: thionyl chloride / dichloromethane 6.1: dichloromethane
  • 38
  • [ 1318242-93-1 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 1.5 h / 0 - 20 °C 2.1: N-ethyl-N,N-diisopropylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / Inert atmosphere 2.2: 20 °C / Inert atmosphere 3.1: sodium hydroxide / tetrahydrofuran / 20 °C 4.1: thionyl chloride / dichloromethane 5.1: dichloromethane
  • 39
  • [ 1388805-29-5 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sodium hydroxide / methanol / 2 h / 30 - 40 °C 2: thionyl chloride / dichloromethane; N,N-dimethyl-formamide / 4 h / 5 - 10 °C 3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C 4: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; tricyclohexylphosphine; caesium carbonate / N,N-dimethyl-formamide / 8 h / 80 °C / Inert atmosphere
  • 40
  • [ 943320-50-1 ]
  • [ 943319-70-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / toluene / 24 h / 58 °C / Inert atmosphere 2: potassium carbonate / methanol / 3 h / 20 °C / Inert atmosphere 3: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; tricyclohexylphosphine; caesium carbonate / N,N-dimethyl-formamide / 8 h / 80 °C / Inert atmosphere
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