CN103664951A - Preparation method of drug for treating chronic granulocytic leukemia - Google Patents
Preparation method of drug for treating chronic granulocytic leukemia Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention relates to a preparation method of a drug for treating chronic granulocytic leukemia, belonging to the field of medical chemistry, and specifically relates to a preparation method of 3-[2-(imidazo[1,2-b] pyridazine-3-yl) acetenyl]-4-methyl-N-{4-[4-methyl piperazine-1-yl] methyl}-3- trifluoromethyl phenyl} benzoyl amide (ponatinib). The method comprises the following steps: adding a phosphine ligand and cesium carbonate at the same time by taking Pd(PPh3)2Cl2 as a catalyst; adding strong base DBU or adding CuI as a cocatalyst to carry out sonagashira reaction, wherein the phosphine ligand is selected from tricyclohexyl phosphine (PCy3), tri-tert-butyl phosphine (PtBu3) or tri(funan-2-yl) phosphine (P(2-furyl)3). The method disclosed by the invention is complete in reaction, does not have or has extremely few diyne byproduct of alkyne coupling, and is easy to separate and purity.
Description
Technical field
The invention belongs to medicinal chemistry arts, it is related to the preparation method for the treatment of for chronic myelocytic leukemia medicine 3- [2- (imidazo [1,2-b] pyridazine -3- bases) acetenyl] -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide (ponatinib).
Background technology
3- [2- (imidazo [1,2-b] pyridazine -3- bases) acetenyl] -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide（Ponatinib）Be Ariad companies exploitation can be used for oral Mutiple Targets enzyme inhibitor, can effectively suppress BCR-ABL regulation signal, indication is chronic myelocytic leukemia（CML）And acute lymphoblastic leukemia with positive Philadelphia chromosome（Ph+ALL）, it is particularly effective to the T315I anomaly chronic myelocytic leukemias of imatinib resistant.
Ponatinib is the BCR-ABL inhibitor of wide spectrum, can suppress BCR-ABL（IC50=0.37nmol/L）And its all mutant, including the T315I variants that various medicines are all resistant to.Preclinical study shows that ponatinib makes a variation to all BCR-ABL shows the inhibitory activity of wide spectrum, in I phase clinical trials, and it is effective in cure that Ponatinib is mutated patient to 66% CML patient and 100% I315I.At present, Ponatinib is in crucial II phase clinical trials.
3- [2- (imidazo [1,2-b] pyridazine -3- bases) acetenyl] -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide（Ponatinib）Chemical constitution it is as follows：
The synthesis Ponatinib reported at present document is few, and synthetic method mainly has following two lines,
Route one：
,
Route two：
X represents to be selected from bromine, the halogen of iodine.
J.Med.Chem.2010(53):4701-4719 reports above-mentioned two lines, but route one is using Pd (PPh3)4/CuI/Et3N conditions carry out sonagashira reactions, and product is mainly the diine accessory substance that alkynes coupling is obtained, cannot get object Ponatinib substantially.
WO2007075869 only reported prepares Ponatinib using route two, in Pd (PPh3)4/CuI/(i-Pr)2Sonagashira reactions are carried out under the conditions of NEt/DMF.
Sonagashira reactivities are influenceed by many factors, such as different halogenated aryl hydrocarbons, and reactivity is significantly different, in general, Ar-I>>Ar-Br>Ar-Cl.In addition, the group of alkynes end connection also has very big influence on reactivity, electron withdraw group activity is substantially better than electron donating group.When the poor substrate of reactivity carries out sonagashira reactions, reactivity height is found, and economic and environment-friendly reaction condition is just extremely important.
The content of the invention
It is an object of the invention to provide new high income, diine by-products content is significantly reduced, it is easy to the Ponatinib preparation methods of purifying.
The present invention has first attempted to bi triphenyl phosphorus palladium chloride（Pd(PPh3)2Cl2）/ cuprous iodide（CuI）For catalyst, triethylamine（Et3N）For alkali, in toluene solvant, 80 DEG C of tube sealing anaerobics reactions, but obtained principal product is the diine thing accessory substance of alkynes coupling, it is impossible to be separated to target product, thus it is speculated that main cause is 3- bromines imidazo [1,2-b] pyridazine reactivity is relatively low, and alkynes copper complex intermediate is more active caused.
The present invention is attempted with Palladium Diacetate（Pd(OAc)2）/ CuI is catalyst, adds tricyclohexyl phosphine（PCy3）Part, DIPEA（DIPEA）For alkali, in DMF solvent, 60 DEG C of tube sealing anaerobics react 16h, and experimental result finds the diine thing accessory substance of obtained mainly alkynes coupling, only micro target product generation is monitored with LC-MS.
The present invention is attempted with four（Triphenylphosphine）Palladium（Pd(PPh3)4）/ CuI is catalyst, during DIPEA is alkali, DMF solvent, and 60 DEG C of tube sealing anaerobics react 16h, can obtain target product, but yield is not high, yield only 30%, and the separation of product is more difficult, even if, purity is still no more than 90% through HPLC after purification.
Trial is not added with CuI, with Pd (PPh3)2Cl2For catalyst, tetrabutyl ammonium fluoride is selected（TBAF）Do in alkali, THF solvents, 18h is reacted under 65 DEG C of inert gas shieldings, target product can be obtained, but yield is not still high, about 21%.
Continue with Pd (PPh3)2Cl2For catalyst, CuI is added without, but select the strong carbon -7- alkene of 1,8- diazabicylos [5.4.0] 11 of alkalescence（DBU）For alkali, in DMF solvent, tube sealing reaction 18h under 80 DEG C of inert gas shieldings can obtain target product with higher yield.
Therefore, the present invention is optimized to the condition, after substantial amounts of condition is groped, it is determined that Pd (PPh3)2Cl2For catalyst, while adding Phosphine ligands and cesium carbonate, add highly basic DBU or addition CuI is used as co-catalyst, reaction is thorough, isolates and purifies easily, primary product is target product, do not find or only find trace alkynes coupled product, wherein, Phosphine ligands are selected from tricyclohexyl phosphine（PCy3）, tri-butyl phosphine（PtBu3）Or three（Furans -2- bases）Phosphine（P(2-furyl)3）.
The present invention is using Pd (PPh3)2Cl2/PCy3/Cs2CO3Condition carries out sonagashira reactions, when doing alkali with DBU, the production almost without diine thing accessory substance, and yield is 50%-60%.When adding CuI co-catalysis simultaneously, it is found that the yield of target product is substantially reduced, and impurity showed increased, thus it is speculated that add after CuI catalysis, DBU's is alkaline too strong, and 3- bromines imidazo [1,2-b] pyridazine itself there occurs elimination reaction.
In addition, equally using Pd (PPh3)2Cl2/PCy3/Cs2CO3Condition carries out sonagashira reactions, when adding CuI co-catalysis, uses DBU instead the weaker organic base of alkalescence, such as DIPEA, Et3N, reaction result is good, and the generation without diine thing accessory substance, yield is not less than 70%；Only add CuI co-catalysis, be not added with any organic base, reaction result is still good, and the generation also without diine thing accessory substance, yield can equally reach more than 70%.
In addition, the method that the present invention is provided additionally provides very big benefit to building Ponatinib derivative diversity, intermediate 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide is built（2）Module, sonagashira reactions are carried out from different halogenated heterocyclics, are that batch synthesis Ponatinib derivatives are provided convenience.
Scheme：
The present invention is with intermediate 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide（2）For raw material, there is provided 2 kinds of synthesis Ponatinib（3）Method, synthetic route is as follows：
,
Method one is by 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide, 3- bromines imidazo [1,2-b] pyridazine, Pd (PPh3)2Cl2、PCy3、Cs2CO3It is dissolved in DBU in DMF solvent, under inert gas shielding, 60-100 DEG C after completion of the reaction, adds ethyl acetate and water extraction, merge organic phase, dry, silicagel column purifying obtains Ponatinib.
Method two is by 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide, 3- bromines imidazo [1,2-b] pyridazine, Pd (PPh3)2Cl2, CuI, PCy3、Cs2CO3It is dissolved in DMF solvent, is not added with or adds organic base DIPEA or Et on a small quantity3N, under inert gas shielding, 60-100 DEG C after completion of the reaction, adds ethyl acetate and water extraction, merges organic phase, dries, and silicagel column purifying obtains Ponatinib.
Wherein, inert gas is selected from conventional nitrogen, argon gas, and reacts conventional ingredient proportion, catalyst Pd (PPh according to sonagashira3)2Cl2Mole be reaction substrate mole 0.5%-10%, PCy3Mole be catalyst Pd (PPh3)2Cl21.0-2.2 times of mole, Cs2CO3Mole be 1-1.2 times of reaction substrate mole, CuI mole is the 1%-10% of reaction substrate mole, DBU mole for reaction substrate mole 5%-20%.
Key intermediate 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide of the present invention（2）Synthesis, can be by J.Med.Chem.2010 (53):The route of 4701-4719 reports, using the methyl benzoic acid of 3- halos -4 as raw material, the step of Deprotection two obtains intermediate 2 after into acid amides, sonagashira reactions, and synthetic route is as follows：
Wherein, X represents halogen, preferably bromine, iodine, most preferably iodine.
Step is as follows：
（i）3- halo -4- methyl-benzoic acids are mixed with thionyl chloride, 78 DEG C of backflows, Rotary Evaporators are removed after volatile substances, it is dissolved in anhydrous tetrahydro furan, add 4- (4- methylpiperazine-1-yls methyl) -3- 5-trifluoromethylanilines, triethylamine, it is stirred at room temperature after completion of the reaction, saturation NaHCO3Solution is washed, and is added ethyl acetate and water extraction, is dried, vacuum distillation removes solvent, silicagel column purifies to obtain 3- halo -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide（1）；（ii）By 3- halo -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide, Pd (PPh3)2Cl2It is dissolved in CuI in organic solvent; add triethylamine and maintain alkaline environment on a small quantity; trimethylsilanylethyn is added under inert gas shielding; after 50-80 DEG C of stirring reaction is finished; ethyl acetate is added into reactant mixture and water is extracted; dry, silicagel column purifying obtains 3- Trimethylsilanylethynyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide.Obtained 3- Trimethylsilanylethynyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide, carbonate are placed in methanol again, under inert gas shielding, reaction is stirred at room temperature.After completion of the reaction, remove methanol under reduced pressure, add ethyl acetate and water is extracted, dry, silicagel column purifying obtains 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide（2）.Wherein, inert gas is selected from nitrogen, argon gas, and organic solvent is selected from toluene, tetrahydrofuran and DMF, and carbonate is selected from potassium carbonate, cesium carbonate etc..
Present invention also offers another new synthetic intermediate 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide（2）Method, synthetic route is as follows：
Wherein, X represents halogen, preferably bromine, iodine, most preferably iodine.Step is as follows：
(i) by compound 4- methyl -3- halogen benzoic acid methyl esters, Pd (PPh3)2Cl2With CuI mixing, under inert gas shielding, trimethylsilyl acetylene, triethylamine are added; 50-80 DEG C of stirring reaction, removes reactant mixture under reduced pressure solvent after completion of the reaction, adds ethyl acetate and water extraction; dry, silica gel column chromatography obtains 4- methyl -3- trimethyl silicane ethyl-acetylene yl benzoic acid methyl esters；
（ii）4- methyl -3- trimethyl silicane ethyl-acetylene yl benzoic acid methyl esters is dissolved in alcoholic solution, alkaline aqueous solution is added dropwise, after the reaction 2 hours of -40 DEG C of room temperature, filtering, concentration, be dissolved in water, filter out insoluble matter, under ice bath be added dropwise diluted acid to pH be 2 or so, filtering, filtrate adds ethyl acetate and water extraction, dries, is concentrated to give 3- acetenyl -4- methyl benzoic acids.Wherein, alcoholic solution is selected from methanol solution, ethanol solution, aqueous isopropanol or their mixture, and alkaline aqueous solution is selected from the NaOH aqueous solution, the LiOH aqueous solution or the KOH aqueous solution.
（iii）3- acetenyl -4- methyl benzoic acids are dissolved in organic solvent, under condition of ice bath, DMF and thionyl chloride is added dropwise, at room temperature after completion of the reaction, reaction solution is concentrated to dryness, add anhydrous tetrahydro furan dissolving, instill in the anhydrous tetrahydrofuran solution equipped with 4- (4- methylpiperazine-1-yls methyl) -3- 5-trifluoromethylanilines, add a small amount of organic base or be not added with organic base, after room temperature reaction is finished, concentration, add water and ethyl acetate extraction, dry, column chromatography purifying obtains 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide（2）.Wherein, organic solvent is selected from dichloromethane, tetrahydrofuran or thionyl chloride, and organic base is selected from DIPEA, Et3N。
Embodiment
The embodiment provided is only used for task of explanation, and is not limited to the present invention.
Embodiment 1：The preparation of 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide
Step A：The preparation of the iodo- 4- methyl-N- of 3- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide：
The iodo- 4- methyl-benzoic acids of 3- are added in round-bottomed flask（2.62g,10mmol）, thionyl chloride 10ml, 78 DEG C are flowed back 4 hours, and Rotary Evaporators remove volatile substances and obtain the iodo- 4- methyl-benzoyl chlorides of 3-.4- (4- methylpiperazine-1-yls methyl) -3- 5-trifluoromethylanilines are added in round-bottomed flask（2.27g,8.3mmol）, the iodo- 4- methyl-benzoyl chlorides of 3-（10mmol）, 15ml tetrahydrofurans, 10ml triethylamines, be stirred at room temperature 4 hours.Use saturation NaHCO3Solution is washed, and adds ethyl acetate and water extraction, the washing of saturation NaCl solution, anhydrous Na2SO4Dry, vacuum distillation removes solvent.Residue purifies to obtain title compound through silicagel column.
1H NMR (500 MHz, CDCl3) δ: 8.39(s,1H,N-H), 8.29(s,1H,Ar-H), 7.88(d,1H,Ar-H),7.86(s, 1H, Ar-H), 7.75(d,1H,Ar-H), 7.73(d,1H,Ar-H), 7.28(d,1H,Ar-H),3.62(s,2H, PhCH2), 2.60(br,8H,-CH2), 2.47(s,3H,-CH3), 2.31(s,3H,-CH3)。
Step B：The preparation of 3- Trimethylsilanylethynyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide
By step A gains (3.1g, 6.1mmol), Pd (PPh3)2Cl2(426mg, 0.61mmol), CuI (231mg, 1.21mmol) are placed in three-necked bottle, are added toluene 30ml and are made solvent, triethylamine 1ml maintains alkaline environment, carry out the circulation of 3 vacuum-refill argon gas.With syringe trimethylsilanylethyn is added into the mixture（3.0g,30.3mmol）, 58 DEG C are stirred 24 hours.Ethyl acetate-water is added into reactant mixture to be extracted, and is merged organic layer, is washed with saturation NaCl solution, adds anhydrous Na2SO4Dry.It is concentrated under reduced pressure, residue purifies to obtain title compound through silicagel column.
1H NMR (500 MHz, CDCl3) δ: 8.30(s,1H,N-H), 7.86(s,1H,Ar-H), 7.83(d,1H,Ar-H),7.72(s, 1H, Ar-H), 7.55(d,1H,Ar-H), 7.41(d,1H,Ar-H), 7.24(d,1H,Ar-H), 3.60(s,2H,PhCH2), 2.48(br,8H,-CH2), 2.45(s,3H,-CH3), 2.28(s,3H,-CH3), 0.26(s,9H,-CH3)。
Step C:The preparation of 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide
Step B gains (1.59g, 3.3mmol), potassium carbonate (1.82g, 13.2mmol), 20ml methanol are mixed in three-necked bottle
In, the circulation of 3 vacuum-refill argon gas is carried out, is stirred at room temperature 3 hours.Methanol is removed under reduced pressure, adds ethyl acetate and water is extracted, merge organic layer, washed with saturation NaCl solution, add anhydrous Na2SO4Dry.Then this is had
Machine solution is concentrated on a rotary evaporator, and residue purifies to obtain target compound through silicagel column.
1H NMR (500 MHz, CDCl3) δ: 10.47(s,1H,N-H), 8.19(s,1H,Ar-H), 8.08(s,1H,Ar-H),8.04(d,1H, Ar-H), 7.91(d,1H,Ar-H), 7.70(d,1H,Ar-H), 7.47(d,1H,Ar-H), 4.50(s,1H,≡CH),3.56(s,2H,PhCH2), 2.50(s,3H,-CH3), 2.36(br,8H,-CH2), 2.15(s,3H,-CH3)。
Embodiment 2：The preparation of 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide
Step A:The preparation of 4- methyl -3- trimethyl silicane ethyl-acetylene yl benzoic acid methyl esters
By 4- methyl -3- iodo-benzoic acid methyl esters (15g, 54.33 mmol), bi triphenyl phosphorus palladium chloride (1.91 g, 2.72 mmol), cuprous iodide (1.03g, 5.43 mmol) it is added in the 50ml neck flask of round bottom two, nitrogen displacement three times, under nitrogen protection, add trimethylsilyl acetylene (21.6mL, 162.99 mmol), triethylamine (12.5 mL, 86.93 mmol), it is heated to 60 DEG C and is stirred overnight reaction, TLC monitoring reactions find that raw material 4- methyl -3- iodo-benzoic acid methyl esters is exhausted, reaction solution removes solvent under reduced pressure, add ethyl acetate and water extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.Vacuum drying, silica gel column chromatography obtains title compound.
1H NMR(CDCl3, 500 MHz): 8.10(d,1H,Ar-H), 7.86(dd,1H, Ar-H), 7.25(d,1H, Ar-H), 3.90(s, 3H, CO2CH3), 2.48(s, 3H, CH3),0.265(s, 9H, 3×CH3)。
Step B：The preparation of the methyl benzoic acid of 3- acetenyls -4
In 100mL single port bottle, step A gains are added（2g, 8.13mmol), methanol 340mL, 2.5N NaOH aqueous solution 13mL (32.5mmol) is added dropwise, during dropwise addition, solution colour is deepened, temperature rises to raw material after 40 DEG C, 2 hours by 30 DEG C and disappeared, filtering, concentration, is dissolved in water, filters out insoluble matter, it is 2 or so that watery hydrochloric acid is added dropwise under ice bath to pH, separates out a large amount of pale solids, plus ethyl acetate and water extraction, dry, concentration obtains title compound.
1H NMR(CDCl3, 500 MHz): 8.20(d,1H,Ar-H), 7.96(dd,1H, Ar-H), 7.32(d, 1H, Ar-H), 3.33(s, 1H,≡CH), 2.53(s, 3H,CH3)。
The preparation of step C 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide
In 20mL round-bottomed flasks, the methyl benzoic acid (480mg, 3mmol) of 3- acetenyls -4 and 10ml dichloromethane are added, under condition of ice bath（5-10℃）, 2d DMF and thionyl chloride 2ml are added dropwise, 4h is reacted, TLC is monitored after completion of the reaction, reaction solution is spin-dried for, the dissolving of 10ml anhydrous tetrahydro furans are added, then instill equipped with 4- (4- methylpiperazine-1-yls methyl) -3- 5-trifluoromethylanilines（616mg, 2mmol）, 40ml anhydrous tetrahydro furans, in 2mlDIPEA 100ml round-bottomed bottles, room temperature reaction is stayed overnight.TLC monitoring reactions are finished, and 40 DEG C of concentrations add 30ml water, use ethyl acetate（30 mL×3）, merge organic phase, anhydrous Na2SO4Dry, concentration, chromatographic purifying obtains target compound.
The 3- of embodiment 3 [2- (imidazo [1,2-b] pyridazine -3- bases) acetenyl] -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide
3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide (126mg is added in 30ml tube sealings, 0.3mmol), 3- bromines imidazo [1,2-b] pyridazine (59mg, 0.3mmol), Pd (PPh3)2Cl2 (11mg,0.02mmol)、PCy3(8mg,0.04mmol)、Cs2CO3(99mg, 0.3mmol), DBU 0.3ml, DMF10ml, lead to argon gas 5 minutes rear encloseds of displaced air, and 80 DEG C are stirred 8 hours.Use ethyl acetate（15ml×4）Extraction, merges organic phase, adds anhydrous Na2SO4Dry.The organic solution is concentrated under reduced pressure, residue is purified through silicagel column, obtains target compound, yield 58%.
1HNMR (CDCl3,500MHz): 8.48(d,1H,Ar-H),8.31(s,1H,Ar-H),8.06(s,1H,-NH),8.06(s,1H, Ar-H), 7.98(d,1H,Ar-H)7.93(d,1H,Ar-H),7.90(s,1H,Ar-H),7.83(q,1H,Ar-H),7.72(d,1H,Ar-H),7.38(d, 1H,Ar-H),7.14(q,1H,Ar-H),3.78(t,2H,PhCH2),2.63(s,3H,-CH3),2.61(b,8H,-CH2),2.43(s,3H,-CH3)。
ESI-MS m/z: [M+H]+=533.3, calculated value 533.2.
The 3- of embodiment 4 [2- (imidazo [1,2-b] pyridazine -3- bases) acetenyl] -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide
3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide (126mg is added in 30ml tube sealings, 0.3mmol), 3- bromines imidazo [1,2-b] pyridazine (59mg, 0.3mmol), Pd (PPh3)2Cl2 (11mg, 0.015mmol), CuI (6mg, 0.03mmol), PCy3(8mg,0.015mmol)、Cs2CO3(99mg, 0.3mmol), DIPEA 0.3ml, DMF10ml, lead to argon gas 5 minutes rear encloseds of displaced air, and 80 DEG C are stirred 8 hours.Use ethyl acetate（15ml×4）Extraction, merges organic layer, adds anhydrous Na2SO4Dry.The organic solution is concentrated under reduced pressure, residue is purified through silicagel column, obtains target compound, yield is 73%.
The 3- of embodiment 5 [2- (imidazo [1,2-b] pyridazine -3- bases) acetenyl] -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide
3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide (126mg is added in 30ml tube sealings, 0.3mmol), 3- bromines imidazo [1,2-b] pyridazine (59mg, 0.3mmol), Pd (PPh3)2Cl2 (11mg, 0.015mmol), CuI (6mg, 0.03mmol), PCy3(8mg,0.015mmol)、Cs2CO3(99mg, 0.3mmol), DMF10ml leads to argon gas 5 minutes rear encloseds of displaced air, and 80 DEG C are stirred 8 hours.Use ethyl acetate（15ml×4）, saturation NaCl solution（30ml）Extracted, merge organic layer, add anhydrous Na2SO4Dry.The organic solution is concentrated under reduced pressure, residue is purified through silicagel column, obtains title compound, yield is 79%.
Embodiment 63- [2- (imidazo [1,2-b] pyridazine -3- bases) acetenyl] -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide
3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide (151mg is added in 30ml tube sealings, 0.36mmol), 3- bromines imidazo [1,2-b] pyridazine (59mg, 0.3mmol), Pd (PPh3)2Cl2(21mg, 0.03mmol), CuI (3mg, 0.015mmol), tricyclohexyl phosphine (17mg, 0.06mmol), cesium carbonate (117mg, 0.36mmol), DMF10ml, leads to nitrogen displacement 5 minutes rear encloseds of air, and 60 DEG C are stirred 18 hours.Use ethyl acetate（15ml×4）, saturation NaCl solution（30ml）Extracted, merge organic layer, add anhydrous Na2SO4Dry.The organic solution is concentrated under reduced pressure, residue obtains title compound through silicagel column, yield is 67%.
Embodiment 73- [2- (imidazo [1,2-b] pyridazine -3- bases) acetenyl] -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide
3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide (126mg is added in 30ml tube sealings, 0.3mmol), 3- bromines imidazo [1,2-b] pyridazinyl (59mg, 0.3mmol), Pd (PPh3)2Cl2(11mg, 0.02mmol), CuI (6mg, 0.015mmol), tricyclohexyl phosphine (8mg, 0.04mmol), cesium carbonate (99mg, 0.3mmol), DMF 10ml, lead to argon gas 5 minutes rear encloseds of displaced air, and 80 DEG C are stirred 8 hours.Use ethyl acetate（15ml×4）Extraction, merges organic phase, adds anhydrous Na2SO4Dry.The organic solution is concentrated under reduced pressure, residue obtains title compound through silicagel column purifying, and yield is 60%.
Claims (10)
1. a kind of 3- [2- (imidazos [1, 2-b] pyridazine -3- bases) acetenyl] and -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide preparation method, it is characterized in that with 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamides and 3- bromines imidazo [1, 2-b] pyridazine be raw material, using bi triphenyl phosphorus palladium chloride as catalyst, add after Phosphine ligands and cesium carbonate, from DBU or from cuprous iodide catalysis, alkynes coupling reaction is carried out to obtain.
2. 3- [2- (imidazos [1 according to claim 1; 2-b] pyridazine -3- bases) acetenyl] and -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide preparation method; with 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamides and 3- bromines imidazo [1; 2-b] pyridazine be raw material; using bi triphenyl phosphorus palladium chloride as catalyst; add Phosphine ligands, cesium carbonate and DBU; under inert gas shielding, 60-100 DEG C of tube sealing reaction.
3. 3- [2- (imidazos [1 according to claim 1; 2-b] pyridazine -3- bases) acetenyl] and -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide preparation method; with 3- acetenyl -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamides and 3- bromines imidazo [1; 2-b] pyridazine be raw material; using bi triphenyl phosphorus palladium chloride as catalyst; add Phosphine ligands, cesium carbonate and cuprous iodide; under inert gas shielding, 60-100 DEG C of tube sealing reaction.
4. according to the 3- [2- (imidazos [1 of claim 1,2 or 3,2-b] pyridazine -3- bases) acetenyl] and -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide preparation method, the Phosphine ligands are tricyclohexyl phosphine, tri-butyl phosphine or three（Furans -2- bases）Phosphine.
5. according to the 3- [2- (imidazos [1 of Claims 2 or 3,2-b] pyridazine -3- bases) acetenyl] and -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide preparation method, described inert gas is selected from nitrogen, argon gas.
6. according to the 3- [2- (imidazos [1 of Claims 2 or 3, 2-b] pyridazine -3- bases) acetenyl] and -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide preparation method, the mole of catalyst bi triphenyl phosphorus palladium chloride is the 0.5%-10% of reaction substrate mole, the mole of Phosphine ligands is 1.0-2.2 times of catalyst bi triphenyl phosphorus palladium chloride mole, the mole of cesium carbonate is 1-1.2 times of reaction substrate mole, the mole of cuprous iodide is the 10% of reaction substrate mole, DBU mole is the 5%-20% of reaction substrate mole.
7. 3- [2- (imidazos [1 according to claim 1,2-b] pyridazine -3- bases) acetenyl] and -4- methyl-N- { 4- [(4- methylpiperazine-1-yls) methyl] -3- trifluoromethyls } benzamide preparation method, wherein 3- acetenyls -4- methyl-N- [4- (4- methylpiperazine-1-yls methyl) -3- trifluoromethyls] benzamide is prepared as follows：3- halos-methyl 4 methylbenzoate carries out alkynes coupling reaction with trimethylsilyl acetylene, then sloughs protection group under alkalescence condition, and acid amides reaction is carried out into 4- (4- methylpiperazine-1-yls methyl) -3- 5-trifluoromethylanilines,
8. method according to claim 7,3- halos-methyl 4 methylbenzoate is 3- iodos-methyl 4 methylbenzoate, 3- bromos-methyl 4 methylbenzoate, preferably 3- iodos-methyl 4 methylbenzoate.
9. method according to claim 7, described alkalescence condition is the alcoholic solution for having added aqueous alkali, aqueous alkali is selected from the NaOH aqueous solution, and the KOH aqueous solution, the LiOH aqueous solution, alcoholic solution is selected from methanol solution, ethanol solution, aqueous isopropanol or their mixture.
10. method according to claim 7; 4- methyl -3- iodo-benzoic acid methyl esters; trimethylsilyl acetylene; bi triphenyl phosphorus palladium chloride, cuprous iodide and triethylamine are under argon gas protection; 50-80 DEG C of reaction obtains 4- methyl -3- trimethyl silicane ethyl-acetylene yl benzoic acid methyl esters, in the methanol solution for being then dissolved in having added the NaOH aqueous solution, room temperature ~ 40 DEG C reaction; dilute acid for adjusting pH obtains the methyl benzoic acid of 3- acetenyls -4 to 2 or so；By under 3- acetenyl -4- methyl benzoic acid ice baths, acyl chlorides is made with thionyl chloride reaction in dichloromethane；Again by gained acyl chlorides in tetrahydrofuran solution with 4- (4- methylpiperazine-1-yls methyl) 0 DEG C of -3- 5-trifluoromethylanilines-react at room temperature.
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| CN108479773A (en) * | 2018-05-30 | 2018-09-04 | 商立华 | A kind of clean preparation method treated leukemia medicament and moor that for Buddhist nun's intermediate |
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| CN105037398A (en) * | 2014-04-16 | 2015-11-11 | 成都大学 | Bcr-Abl amphiploid inhibitor, preparation method and application thereof |
| CN105037398B (en) * | 2014-04-16 | 2017-10-24 | 深圳永泽医药股份有限公司 | A kind of Bcr Abl amphiploid inhibitor and its production and use |
| CN108479773A (en) * | 2018-05-30 | 2018-09-04 | 商立华 | A kind of clean preparation method treated leukemia medicament and moor that for Buddhist nun's intermediate |
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