CN103664951B - A kind of preparation method treating chronic myelocytic leukemia medicine - Google Patents
A kind of preparation method treating chronic myelocytic leukemia medicine Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Abstract
Invent a kind of preparation method treating chronic myelocytic leukemia medicine and belong to medicinal chemistry arts, it is specifically related to 3 [2 (imidazos [1,2 b] pyridazine 3 base) acetenyl] preparation method of 4 methyl N { 4 [(4 methyl piperazine 1 base) methyl] 3 trifluoromethyls } Benzoylamide (ponatinib), the method is with Pd (PPh3)2Cl2For catalyst, it is simultaneously introduced Phosphine ligands and cesium carbonate, adds highly basic DBU or add CuI as promoter, carrying out sonagashira reaction.Wherein, Phosphine ligands is selected from tricyclohexyl phosphine (PCy3), tri-butyl phosphine (PtBu3) or three (furan 2 base) phosphine (P (2 furyl)3).The method reaction thoroughly, does not has or seldom produces a diine by-product of alkynes coupling, isolated and purified easily.
Description
Technical field
The invention belongs to medicinal chemistry arts, relate to treatment for chronic myelocytic leukemia medicine 3-[2-(imidazo [1,2-
B] pyridazine-3-base) acetenyl]-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-trifluoromethyl } benzoyl
The preparation method of amine (ponatinib).
Background technology
3-[2-(imidazo [1,2-b] pyridazine-3-base) acetenyl]-4-methyl-N-{4-[(4-methylpiperazine-1-yl) first
Base]-3-trifluoromethyl Benzoylamide (Ponatinib) be Ariad company exploitation the Mutiple Targets enzyme that can be used for being administered orally press down
Preparation, it is possible to the effectively signal of suppression BCR-ABL regulation, indication is chronic myelocytic leukemia (CML) and Philadelphia chromosome
Positive Acute Lymphoblastic Leukemia (Ph+ALL), particularly white to the T315I anomaly chronic granulocyte of imatinib resistant
Disorders of blood is effective.
Ponatinib is the BCR-ABL inhibitor of wide spectrum, can suppress BCR-ABL (IC50=0.37nmol/L) and all
Mutant, including the T315I variant all tolerated various medicines.Preclinical study shows, ponatinib is to all
BCR-ABL variation demonstrates the inhibitory activity of wide spectrum, in I phase clinical experiment, the Ponatinib CML patient and 100% to 66%
I315I sudden change patient effective in cure.At present, Ponatinib is in the II phase clinical trial of key.
3-[2-(imidazo [1,2-b] pyridazine-3-base) acetenyl]-4-methyl-N-{4-[(4-methylpiperazine-1-yl) first
Base]-3-trifluoromethyl } chemical constitution of Benzoylamide (Ponatinib) is as follows:
The document of the synthesis Ponatinib of report is few at present, and synthetic method mainly has following two lines,
Route one:
Route two:
,
X represents selected from bromine, the halogen of iodine.
J.Med.Chem.2010 (53): 4701-4719 reports above-mentioned two lines, but route one uses Pd
(PPh3)4/CuI/Et3N condition carries out sonagashira reaction, the product diine by-product that mainly alkynes coupling obtains, substantially
Can not get object Ponatinib.
WO2007075869 only reported employing route two and prepares Ponatinib, at Pd (PPh3)4/CuI/(i-Pr)2Sonagashira reaction is carried out under the conditions of NEt/DMF.
Sonagashira reactivity is affected by many factors, and such as different halogenated aryl hydrocarbons, reactivity is the most not
With, in general, Ar-I > > Ar-Br > Ar-Cl.Additionally, the group that alkynes end connects also has the biggest shadow to reactivity
Ringing, electron withdraw group activity is substantially better than electron donating group.The substrate poor when reactivity carries out sonagashira reaction,
Searching reactivity is high, and economic and environment-friendly reaction condition is the most extremely important.
Summary of the invention
It is an object of the invention to provide new yield high, diine by-products content significantly reduces, it is easy to purification
Ponatinib preparation method.
The present invention has first attempted to bi triphenyl phosphorus palladium chloride (Pd (PPh3)2Cl2)/Hydro-Giene (Water Science). (CuI) is catalysis
Agent, triethylamine (Et3N) it is alkali, in toluene solvant, 80 DEG C of tube sealing anaerobic reactions, but the principal product obtained is the two of alkynes coupling
Alkynes thing by-product, it is impossible to be separated to target product, thus it is speculated that main cause be 3-bromine imidazo [1,2-b] pyridazine reactivity relatively
Low, and alkynes copper complex intermediate is more active caused.
The present invention attempts with Palladium Diacetate (Pd (OAc)2)/CuI is catalyst, adds tricyclohexyl phosphine (PCy3) part, N,
N-diisopropylethylamine (DIPEA) is alkali, and in DMF solvent, 60 DEG C of tube sealing anaerobic reaction 16h, experimental result finds the master obtained
If the diine thing by-product of alkynes coupling, the target product monitoring only trace with LC-MS generates.
The present invention attempts with tetrakis triphenylphosphine palladium (Pd (PPh3)4)/CuI is catalyst, and DIPEA is alkali, in DMF solvent,
60 DEG C of tube sealing anaerobic reaction 16h, it is possible to obtain target product, but productivity is the highest, yield only 30%, and the separation of product is the most tired
Difficulty, even if through HPLC after purification, purity is still less than 90%.
Trial is not added with CuI, with Pd (PPh3)2Cl2For catalyst, tetrabutyl ammonium fluoride (TBAF) is selected to do alkali, THF solvent
In, react 18h under 65 DEG C of inert gas shieldings, it is possible to obtain target product, but productivity is the highest, about 21%.
Continue with Pd (PPh3)2Cl2For catalyst, be added without CuI, but select alkalescence strong 1,8-diazabicylo
[5.4.0] 11 carbon-7-alkene (DBU) is alkali, in DMF solvent, and tube sealing reaction 18h under 80 DEG C of inert gas shieldings, can be with relatively
High yield obtains target product.
Therefore, this condition is optimized by the present invention, after substantial amounts of condition is groped, it is determined that Pd (PPh3)2Cl2For
Catalyst, is simultaneously introduced Phosphine ligands and cesium carbonate, adds highly basic DBU or adds CuI as promoter, and reaction thoroughly, separates
Purification is easy, and primary product is target product, does not find or only find trace alkynes coupled product, and wherein, Phosphine ligands is selected from three
Cyclohexyl phosphine (PCy3), tri-butyl phosphine (PtBu3) or three (furan-2-base) phosphine (P (2-furyl)3).
The present invention uses Pd (PPh3)2Cl2/PCy3/Cs2CO3Condition carries out sonagashira reaction, when doing alkali with DBU
Time, almost without the production of diine thing by-product, productivity is 50%-60%.When being simultaneously introduced CuI co-catalysis, find that target is produced
The productivity of thing is substantially reduced, and impurity showed increased, thus it is speculated that after adding CuI catalysis, the alkalescence of DBU is too strong, 3-bromine imidazo [1,
2-b] pyridazine self there occurs elimination reaction.
It addition, use Pd (PPh equally3)2Cl2/PCy3/Cs2CO3Condition carries out sonagashira reaction, when adding CuI
Co-catalysis, uses the organic base that alkalescence is more weak instead, such as DIPEA, Et by DBU3N, reaction result is good, does not has diine thing by-product
Producing, productivity is not less than 70%；Only adding CuI co-catalysis, be not added with any organic base, reaction result is still good, does not also have diine thing
The generation of by-product, productivity can reach more than 70% equally.
Additionally, the method that the present invention provides additionally provides the biggest benefit, structure to building Ponatinib derivant multiformity
Build up intermediate 3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl] Benzoylamide
(2) module, carries out sonagashira reaction from different halogenated heterocyclics, provides just for batch synthesis Ponatinib derivant
Profit.
Scheme:
The present invention is with intermediate 3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethylbenzene
Base] Benzoylamide (2) is raw material, it is provided that 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-yl methyl)-3-trifluoromethyl]
Benzoylamide, 3-bromine imidazo [1,2-b] pyridazine, Pd (PPh3)2Cl2、PCy3、Cs2CO3It is dissolved in DMF solvent with DBU, inertia
Under gas shield, 60-100 DEG C after completion of the reaction, adds ethyl acetate and water extraction, merges organic facies, be dried, silica column purification
Obtain Ponatinib.
Method two is by 3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl]
Benzoylamide, 3-bromine imidazo [1,2-b] pyridazine, Pd (PPh3)2Cl2, CuI, PCy3、Cs2CO3Be dissolved in DMF solvent, be not added with or
A small amount of addition organic base DIPEA or Et3N, under inert gas shielding, 60-100 DEG C after completion of the reaction, adds ethyl acetate and water
Extraction, merges organic facies, is dried, and silica column purification obtains Ponatinib.
Wherein, noble gas is selected from conventional nitrogen, argon, and reacts conventional ingredient proportion according to sonagashira,
Catalyst Pd (PPh3)2Cl2The 0.5%-10% that mole is reaction substrate mole, PCy3Mole be catalyst Pd
(PPh3)2Cl21.0-2.2 times of mole, Cs2CO31-1.2 times that mole is reaction substrate mole, the mole of CuI
For the 1%-10% of reaction substrate mole, the mole of DBU is the 5%-20% of reaction substrate mole.
Key intermediate 3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl the methyl)-3-fluoroform of the present invention
Base phenyl] synthesis of Benzoylamide (2), can be by the route of J.Med.Chem.2010 (53): 4701-4719 report, with 3-halogen
In generation ,-4 ar-Toluic acids were raw material, and after becoming amide, sonagashira reaction, Deprotection two step obtains intermediate 2, synthesis
Route is as follows:
,
Wherein, X represents halogen, preferably bromine, iodine, most preferably iodine.
Step is as follows:
(i) 3-halo-4-methyl-benzoic acid mixes with thionyl chloride, 78 DEG C of backflows, and Rotary Evaporators removes effumability
After material, it is dissolved in anhydrous tetrahydro furan, adds 4-(4-methylpiperazine-1-yl methyl)-3-5-trifluoromethylaniline, triethylamine,
It is stirred at room temperature after completion of the reaction, saturated NaHCO3Solution washs, and adds ethyl acetate and water extraction, is dried, and decompression is distilled off
Solvent, silica column purification obtains 3-halo-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl] benzene first
Amide (1)；(ii) by 3-halo-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl] benzoyl
Amine, Pd (PPh3)2Cl2Being dissolved in organic solvent with CuI, addition triethylamine maintains on a small quantity and adds under alkaline environment, inert gas shielding
Entering trimethylsilanylethyn, 50-80 DEG C of stirring after completion of the reaction, adds ethyl acetate in reactant mixture and water extracts
Take, be dried, silica column purification obtain 3-Trimethylsilanylethynyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-
3-trifluoromethyl] Benzoylamide.3-Trimethylsilanylethynyl-4-methyl-N-[4-(the 4-methyl piperazine that will obtain again
Piperazine-1-ylmethyl)-3-trifluoromethyl] Benzoylamide, carbonate is placed in methanol, under inert gas shielding, is stirred at room temperature
Reaction.After completion of the reaction, removing methanol under reduced pressure, add ethyl acetate and water extracts, be dried, silica column purification obtains 3-second
Alkynyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl] Benzoylamide (2).Wherein, indifferent gas
Body is selected from nitrogen, argon, and organic solvent is selected from potassium carbonate, cesium carbonate etc. selected from toluene, oxolane and DMF, carbonate.
Present invention also offers another kind of new synthetic intermediate 3-acetenyl-4-methyl-N-[4-(4-methyl piperazine-1-
Ylmethyl)-3-trifluoromethyl] method of Benzoylamide (2), synthetic route is as follows:
,
Wherein, X represents halogen, preferably bromine, iodine, most preferably iodine.Step is as follows:
I () is by compound 4-methyl-3-halogen benzoic acid methyl ester, Pd (PPh3)2Cl2Mix with CuI, inert gas shielding
Under, add trimethylsilyl acetylene, triethylamine, 50-80 DEG C of stirring reaction, after completion of the reaction reactant mixture is removed under reduced pressure molten
Agent, adds ethyl acetate and water extraction, is dried, and silica gel column chromatography obtains 4-methyl-3-trimethyl silicane ethyl-acetylene yl benzoic acid first
Ester；
(ii) 4-methyl-3-trimethyl silicane ethyl-acetylene yl benzoic acid methyl ester is dissolved in alcoholic solution, drips alkaline aqueous solution,
After room temperature-40 DEG C is reacted 2 hours, filtering, concentrate, be dissolved in water, filter out insoluble matter, dripping diluted acid under ice bath is 2 to pH
Left and right, filters, and filtrate adds ethyl acetate and water extraction, is dried, is concentrated to give 3-acetenyl-4-ar-Toluic acid.Wherein, alcohol
Solution is selected from NaOH aqueous solution selected from methanol solution, ethanol solution, aqueous isopropanol or their mixture, alkaline aqueous solution,
LiOH aqueous solution or KOH aqueous solution.
(iii) 3-acetenyl-4-ar-Toluic acid is dissolved in organic solvent, under condition of ice bath, dropping DMF and protochloride
Sulfone, under room temperature after completion of the reaction, is concentrated to dryness reactant liquor, adds anhydrous tetrahydro furan and dissolves, instills equipped with 4-(4-methyl piperazine
Piperazine-1-ylmethyl)-3-5-trifluoromethylaniline anhydrous tetrahydrofuran solution in, add a small amount of organic base or be not added with organic base,
After room temperature reaction, concentrate, add water and ethyl acetate extraction, be dried, column chromatography purification obtain 3-acetenyl-4-methyl-
N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl] Benzoylamide (2).Wherein, organic solvent is selected from dichloromethane
Alkane, oxolane or thionyl chloride, organic base is selected from DIPEA, Et3N。
Detailed description of the invention
The embodiment be given is only used for task of explanation, and is not limited to the present invention.
Embodiment 1:3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl] benzene
The preparation of Methanamide
Step A:3-iodo-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl] Benzoylamide
Preparation:
Adding 3-iodo-4-methyl-benzoic acid (2.62g, 10mmol), thionyl chloride 10ml in round-bottomed flask, 78 DEG C are returned
Flowing 4 hours, Rotary Evaporators removes volatile substances and obtains 3-iodo-4-methyl-benzoyl chloride.4-is added in round-bottomed flask
(4-methylpiperazine-1-yl methyl)-3-5-trifluoromethylaniline (2.27g, 8.3mmol), 3-iodo-4-methyl-benzoyl chloride
(10mmol), 15ml oxolane, 10ml triethylamine, be stirred at room temperature 4 hours.Use saturated NaHCO3Solution washs, and adds acetic acid
Ethyl ester and water extraction, the washing of saturated NaCl solution, anhydrous Na2SO4Being dried, decompression is distilled off solvent.Residue is pure through silicagel column
Change to obtain title compound.
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:3-Trimethylsilanylethynyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-fluoroform
Base phenyl] preparation of Benzoylamide
By step A gains (3.1g, 6.1mmol), Pd (PPh3)2Cl2(426mg,0.61mmol)、CuI(231mg,
1.21mmol) being placed in three-necked bottle, add toluene 30ml and make solvent, triethylamine 1ml maintains alkaline environment, carries out 3 vacuum-again
It is full of the circulation of argon.Adding trimethylsilanylethyn (3.0g, 30.3mmol) in this mixture with syringe, 58 DEG C are stirred
Mix 24 hours.In reactant mixture, add ethyl acetate water extract, merge organic layer, wash by saturated NaCl solution
Wash, add anhydrous Na2SO4It is dried.Concentrating under reduced pressure, residue obtains title compound through silica column purification.
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:3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl] benzene first
The preparation of amide
By step B gains (1.59g, 3.3mmol), potassium carbonate (1.82g, 13.2mmol), 20ml methanol mixed in three
Neck bottle
In, carry out the circulation of 3 vacuum-refill argon, be stirred at room temperature 3 hours.Decompression removes methanol, adds acetic acid second
Ester and water extract, and merge organic layer, wash by saturated NaCl solution, add anhydrous Na2SO4It is dried.Then this is had
Machine solution concentrates on a rotary evaporator, and residue obtains target compound through silica column purification.
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 2:3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl] benzene
The preparation of Methanamide
The preparation of step A:4-methyl-3-trimethyl silicane ethyl-acetylene yl benzoic acid methyl ester
By 4-methyl-3-iodo-benzoic acid methyl ester (15g, 54.33 mmol), bi triphenyl phosphorus palladium chloride (1.91 g,
2.72 mmol), Hydro-Giene (Water Science). (1.03g, 5.43 mmol) joins in the round bottom two neck flask of 50ml, and nitrogen is replaced three times,
Under nitrogen protection, add trimethylsilyl acetylene (21.6mL, 162.99 mmol), triethylamine (12.5 mL, 86.93 mmol),
Being heated to 60 DEG C and be stirred overnight reaction, TLC monitoring reaction finds that raw material 4-methyl-3-iodo-benzoic acid methyl ester is exhausted, reaction
Liquid removes solvent under reduced pressure, adds ethyl acetate and water extraction, merges organic facies, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried.
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)。
The preparation of step B:3-acetenyl-4 ar-Toluic acid
In the single port bottle of 100mL, add step A gains (2g, 8.13mmol), methanol 340mL, drip 2.5N's
NaOH aqueous solution 13mL (32.5mmol), during dropping, solution colour deepens, and temperature is risen to 40 DEG C by 30 DEG C, after 2 hours
Raw material disappears, and filters, and concentrates, is dissolved in water, filters out insoluble matter, and dripping dilute hydrochloric acid under ice bath is about 2 to pH, separates out big
Amount pale solid, adds ethyl acetate and water extraction, is dried, concentrates, obtain 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)。
Step C 3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl] benzene first
The preparation of amide
In 20mL round-bottomed flask, add 3-acetenyl-4 ar-Toluic acid (480mg, 3mmol) and 10ml dichloromethane,
Under condition of ice bath (5-10 DEG C), dripping 2d DMF and thionyl chloride 2ml, reaction 4h, TLC monitor after completion of the reaction, will reaction
Liquid is spin-dried for, and adds 10ml anhydrous tetrahydro furan and dissolves, then instills equipped with 4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl
Aniline (616mg, 2mmol), 40ml anhydrous tetrahydro furan, in the 100ml round-bottomed bottle of 2mlDIPEA, room temperature reaction is overnight.TLC supervises
Measured reaction is complete, 40 DEG C of concentrations, adds the water of 30ml, with ethyl acetate (30 mL × 3), merges organic facies, anhydrous Na2SO4Dry
Dry, concentrate, chromatography purification obtains target compound.
Embodiment 3 3-[2-(imidazo [1,2-b] pyridazine-3-base) acetenyl]-4-methyl-N-{4-[(4-methyl piperazine
Piperazine-1-base) methyl]-3-trifluoromethyl } Benzoylamide
3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl is added in 30ml tube sealing
Phenyl] Benzoylamide (126mg, 0.3mmol), 3-bromine 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 are logical
5 minutes rear encloseds of argon displaced air, 80 DEG C are stirred 8 hours.Extract by ethyl acetate (15ml × 4), merge organic facies, add
Anhydrous Na2SO4It is dried.By this organic solution concentrating under reduced pressure, residue, through silica column purification, obtains target compound, productivity 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, value of calculation 533.2.
Embodiment 4 3-[2-(imidazo [1,2-b] pyridazine-3-base) acetenyl]-4-methyl-N-{4-[(4-methyl piperazine
Piperazine-1-base) methyl]-3-trifluoromethyl } Benzoylamide
3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl is added in 30ml tube sealing
Phenyl] Benzoylamide (126mg, 0.3mmol), 3-bromine 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, logical 5 minutes rear encloseds of argon displaced air, 80 DEG C are stirred 8 hours.With ethyl acetate (15ml
× 4) extraction, merges organic layer, adds anhydrous Na2SO4It is dried.By this organic solution concentrating under reduced pressure, residue is pure through silicagel column
Changing, obtain target compound, productivity is 73%.
Embodiment 5 3-[2-(imidazo [1,2-b] pyridazine-3-base) acetenyl]-4-methyl-N-{4-[(4-methyl piperazine
Piperazine-1-base) methyl]-3-trifluoromethyl } Benzoylamide
3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl is added in 30ml tube sealing
Phenyl] Benzoylamide (126mg, 0.3mmol), 3-bromine 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, logical 5 minutes rear encloseds of argon displaced air, 80 DEG C are stirred 8 hours.With ethyl acetate (15ml × 4), saturated NaCl
Solution (30ml) extracts, and merges organic layer, adds anhydrous Na2SO4It is dried.By this organic solution concentrating under reduced pressure, residue warp
Silica column purification, obtains title compound, and productivity is 79%.
Embodiment 6 3-[2-(imidazo [1,2-b] pyridazine-3-base) acetenyl]-4-methyl-N-{4-[(4-methyl piperazine
Piperazine-1-base) methyl]-3-trifluoromethyl } Benzoylamide
3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl is added in 30ml tube sealing
Phenyl] Benzoylamide (151mg, 0.36mmol), 3-bromine 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, logical 5 minutes rear encloseds of nitrogen displaced air, 60 DEG C are stirred 18 hours.With ethyl acetate (15ml ×
4), saturated NaCl solution (30ml) extract, merge organic layer, add anhydrous Na2SO4It is dried.By dense for the decompression of this organic solution
Contracting, residue obtains title compound through silicagel column, and productivity is 67%.
Embodiment 7 3-[2-(imidazo [1,2-b] pyridazine-3-base) acetenyl]-4-methyl-N-{4-[(4-methyl piperazine
Piperazine-1-base) methyl]-3-trifluoromethyl } Benzoylamide
3-acetenyl-4-methyl-N-[4-(4-methylpiperazine-1-yl methyl)-3-trifluoromethyl is added in 30ml tube sealing
Phenyl] Benzoylamide (126mg, 0.3mmol), 3-bromine 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, logical 5 minutes rear encloseds of argon displaced air, 80 DEG C are stirred 8 hours.With ethyl acetate (15ml × 4)
Extraction, merges organic facies, adds anhydrous Na2SO4It is dried.By this organic solution concentrating under reduced pressure, residue obtains through silica column purification
Title compound, productivity is 60%.
Claims (10)
1. the preparation method of a ponatinib, it is characterised in that with 3-acetenyl-4-methyl-N-[4-(4-methyl piperazine-1-
Ylmethyl)-3-trifluoromethyl] Benzoylamide and 3-bromine imidazo [1,2-b] pyridazine be raw material, with bi triphenyl phosphorus dichloro
Change palladium is catalyst, adds Phosphine ligands, cesium carbonate and DBU, under inert gas shielding, 60-100 DEG C of tube sealing reaction.
2. the preparation method of a ponatinib, it is characterised in that with 3-acetenyl-4-methyl-N-[4-(4-methyl piperazine-1-
Ylmethyl)-3-trifluoromethyl] Benzoylamide and 3-bromine imidazo [1,2-b] pyridazine be raw material, with bi triphenyl phosphorus dichloro
Change palladium is catalyst, adds Phosphine ligands, cesium carbonate and Hydro-Giene (Water Science)., under inert gas shielding, 60-100 DEG C of tube sealing reaction.
3., according to the preparation method of the ponatinib of claim 1 or 2, wherein said Phosphine ligands is tricyclohexyl phosphine, three tertiary fourths
Base phosphine or three (furan-2-base) phosphine.
4., according to the preparation method of the ponatinib of claim 1 or 2, wherein said noble gas is selected from nitrogen and argon.
5. according to the preparation method of the ponatinib of claim 1 or 2, wherein the rubbing of catalyst bi triphenyl phosphorus palladium chloride
Your amount is the 0.5%-10% of reaction substrate mole, and the mole of Phosphine ligands is catalyst bi triphenyl phosphorus palladium chloride mole
1.0-2.2 times of amount, the mole of cesium carbonate is 1-1.2 times of reaction substrate mole, and the mole of Hydro-Giene (Water Science). is reaction
The 10% of substrate mole, the mole of DBU is the 5%-20% of reaction substrate mole.
6. according to the preparation method of the ponatinib of claim 1 or 2, wherein 3-acetenyl-4-methyl-N-[4-(4-methyl
Piperazine-1-ylmethyl)-3-trifluoromethyl] Benzoylamide is prepared as follows: 3-halo-methyl 4 methylbenzoate
Carry out alkynes coupling reaction with trimethylsilyl acetylene, then slough protection group under the conditions of alkalescence, with 4-(4-methylpiperazine-1-yl first
Base)-3-5-trifluoromethylaniline carry out into amide reaction,
Method the most according to claim 6, wherein 3-halo-methyl 4 methylbenzoate is 3-iodo-4-ar-Toluic acid first
Ester or 3-bromo-methyl 4 methylbenzoate.
Method the most according to claim 6, wherein 3-halo-methyl 4 methylbenzoate is 3-iodo-4-ar-Toluic acid first
Ester.
Method the most according to claim 6, described alkaline condition is to have added the alcoholic solution of aqueous alkali, and aqueous alkali is selected from
NaOH aqueous solution, KOH aqueous solution, LiOH aqueous solution, alcoholic solution selected from methanol solution, ethanol solution, aqueous isopropanol or they
Mixture.
Method the most according to claim 6, it is characterised in that described 3-halo-methyl 4 methylbenzoate is 4-methyl-3-iodine
For essence of Niobe, described concrete preparation method include by 4-methyl-3-iodobenzoic acid methyl ester, trimethylsilyl acetylene, double three
Phenyl phosphorus palladium chloride, Hydro-Giene (Water Science). and triethylamine are under argon shield, and 50-80 DEG C of reaction obtains 4-methyl-3-trimethyl silicane
Ethyl-acetylene yl benzoic acid methyl ester, is then dissolved in having added in the methanol solution of NaOH aqueous solution, room temperature～40 DEG C of reactions, diluted acid
Regulation pH to about 2, obtains 3-acetenyl-4 ar-Toluic acid；By under 3-acetenyl-4-ar-Toluic acid ice bath, dichloromethane
In with thionyl chloride react prepare acyl chlorides；Again by upper step gained acyl chlorides in tetrahydrofuran solution with 4-(4-methylpiperazine-1-yl
Methyl) under 0 DEG C-room temperature of-3-5-trifluoromethylaniline reaction and obtain.
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| Discovery of 3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)-methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitorof Breakpoint Cluster Region-Abelson (BCR-ABL) Kinase Including the;Wei-Sheng Huang，et al;《Journal of Medicinal Chenmistry》;20100601;第53卷(第12期);4703页shceme2，4713页右栏最后一段倒数第6和7行、4715页左栏第5段、4716页右栏第4段 * |
| Rapid and Efficient Pd-Catalyzed Sonogashira Coupling of Aryl Chloride;He Huang，et al;《Journal of Organic Chemistry》;20080704;第73卷(第15期);6037页Table1的Entry9 * |
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