CN104496995A - Method for preparing 3-ethynylimidazo[1,2-b]pyridazine - Google Patents
Method for preparing 3-ethynylimidazo[1,2-b]pyridazine Download PDFInfo
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- CN104496995A CN104496995A CN201410753303.0A CN201410753303A CN104496995A CN 104496995 A CN104496995 A CN 104496995A CN 201410753303 A CN201410753303 A CN 201410753303A CN 104496995 A CN104496995 A CN 104496995A
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- DIXLJLOIQUHTAS-UHFFFAOYSA-N CC(C)(C#Cc1cnc2[n]1nccc2)O Chemical compound CC(C)(C#Cc1cnc2[n]1nccc2)O DIXLJLOIQUHTAS-UHFFFAOYSA-N 0.000 description 2
- 0 CC(Cc1cc(*)c(C*2CC*(C)CC2)cc1)C(C)C(c(cc1C#CC2=C*C3=CC=C**23)ccc1NC)=O Chemical compound CC(Cc1cc(*)c(C*2CC*(C)CC2)cc1)C(C)C(c(cc1C#CC2=C*C3=CC=C**23)ccc1NC)=O 0.000 description 1
Classifications
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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
- C07D295/06—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 halogen atoms or nitro radicals
- C07D295/073—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 halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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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
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a method for preparing 3-ethynylimidazo[1,2-b]pyridazine (a compound 2). The method comprises the step of mixing 4-(imidazo[1,2-b]pyridazine-3-yl)-2-methyl-3-butyne-2-ol (a compound 3) with alkali for reacting in a solvent. According to the method for preparing the compound 2 from the compound 3, the compound 3 is in a solid state and is stable in properties, and can be used as a medicine intermediate; due to cheap and easily available raw material 2-methyl-3-butyne-2-ol or other reagents needed by preparing the compound 3, the cost is low; the reaction is mild in conditions and suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry intermediate field, be specifically related to the method that one prepares 3-ethynyl imidazo [1,2-b] pyridazine.
Background technology
PCT application WO 2007075869 discloses acetylenic heteroaryl compounds of a class novelty and preparation method thereof with them at Therapeutic cancer, osteopathia, metabolic trouble, purposes in inflammatory diseases and Other diseases, wherein 3-(imidazo [1, 2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-(4-((4-methylpiperazine-1-yl)-methyl)-3-(trifluoromethyl) phenyl) benzamide is (Compound I a) or its pharmacy acceptable salt, for orally active Mutiple Targets kinase inhibitor, it is the most potent BCR-ABL inhibitor disclosed in so far and first pan-BCR-ABL inhibitor that can suppress all known mutations forms of target spot (comprising the T315I mutant strain to other medicines resistance cannot treated at present),
PCT application WO 2007075869 reports with reagent such as 4-nitro-2-trifluoromethyl toluene (1) as raw material, 3-(imidazo [1 is obtained through 8 step reaction, 2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-(4-((4-methylpiperazine-1-yl)-methyl)-3-(trifluoromethyl) phenyl) benzamide (compound 1), wherein, the reaction of final step is as follows:
Compound 8 and compound 2 carry out Sonogashira linked reaction and obtain compound 1.
Summary of the invention
One prepares the method for 3-ethynyl imidazo [1,2-b] pyridazine (compound 2),
It comprises, and in a solvent, 4-(imidazo [1,2-b] pyridazine-3-base)-2-methyl-3-butyne-2-alcohol (compound 3) mixes with alkali and reacts,
Described alkali is alkalimetal hydride, alkaline earth metal hydride, alkali metal hydroxide, alkaline earth metal hydroxides or its combination.In certain embodiments, described alkali is sodium hydride, potassium hydride KH, hydrolith, sodium hydroxide, lithium hydroxide, potassium hydroxide or its combination; In certain embodiments, the compound 3 relative to 1.0 moles, the consumption of described alkali is about 2.0 moles to about 6.0 moles, is about 4.0 moles in certain embodiments.
The solvent used is not particularly limited, as long as can dissolve raw material to a certain extent and the solvent of inhibited reaction can not use here, in certain embodiments, described solvent is that aromatic hydrocarbon solvent is as benzene, toluene or dimethylbenzene or its combination.In certain embodiments, the temperature of reaction of described reaction is about 40 degrees Celsius of reflux temperatures to reaction system.
A new compound, 4-(imidazo [1,2-b] pyridazine-3-base)-2-methyl-3-butyne-2-alcohol, its structure is such as formula shown in (3):
Described compound 3 is prepared by the following method, and it comprises: obtained through Sonogashira linked reaction by compound 4 and 2-methyl-3-butyne-2-alcohol (compound 5),
Wherein, L is methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl or halogen group (as Cl, Br or I), and L is Br in certain embodiments, and in further embodiments, L is Cl, and in certain embodiments, L is I.
In certain embodiments, described Sonogashira linked reaction is carried out in ether solvent, aromatic hydrocarbon solvent or ether solvent and the mixed solvent of water or the mixed solvent of aromatic hydrocarbon solvent and water, in certain embodiments, described ether solvent is tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, dimethoxy, diethylene glycol dimethyl ether, triglyme or its combination.In further embodiments, described aromatic hydrocarbon solvent is benzene,toluene,xylene or its combination.In further embodiments, Sonogashira linked reaction is carried out in the mixed solvent of toluene and water, in certain embodiments, Sonogashira linked reaction is carried out in the mixed solvent of tetrahydrofuran (THF) and water, in a certain embodiment, Sonogashira linked reaction is carried out in the mixed solvent of 2-methyltetrahydrofuran and water, and in certain embodiments, the solvent of Sonogashira linked reaction is the mixed solvent of dimethylbenzene and water.
In certain embodiments, described Sonogashira linked reaction can be carried out under base catalysis, and described alkali is salt of wormwood K
2cO
3, sodium carbonate Na
2cO
3, cesium carbonate Cs
2cO
3, saleratus KHCO
3, sodium bicarbonate NaHCO
3, potassiumphosphate K
3pO
4, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU) or diethylamine or its combination, in certain embodiments, described alkali is salt of wormwood or sodium carbonate or its combination, in certain embodiments, compound 4 relative to 1 mole, the consumption of described alkali is about 2 moles to about 4.0 moles, is about 3.0 moles in certain embodiments.
In certain embodiments, described Sonogashira linked reaction is carried out under palladium catalyst exists, and described palladium catalyst is tetrakis triphenylphosphine palladium, two (triphenylphosphine) palladium chloride, Pd/C-triphenylphosphine, PdCl
2-triphenylphosphine or its combination, in certain embodiments, described palladium catalyst is tetrakis triphenylphosphine palladium; The consumption of described palladium catalyst, in certain embodiments, the compound 3 relative to 1 mole, the consumption of described palladium catalyst is about 3% mole to about 10% mole, and in certain embodiments, the consumption of catalyzer is about 5% mole.
In certain embodiments, described Sonogashira linked reaction is carried out under copper catalyst exists, described copper catalyst is cuprous chloride CuCl, bromize alpha ketone CuBr, the sub-ketone CuI of iodate or its combination, and in certain embodiments, described copper catalyst is CuI; The consumption of described copper catalyst, in certain embodiments, the compound 4 relative to 1 mole, the consumption of described copper catalyst is about 6% mole to about 20% mole, and in certain embodiments, the consumption of copper catalyst is 10% mole.
In certain embodiments, the temperature of reaction of described Sonogashira linked reaction is about 40 degrees Celsius to about 100 degrees Celsius, and temperature of reaction is in further embodiments about 70 degrees Celsius to about 90 degrees Celsius.
Compound 3 provided by the present invention prepares the method for compound 2, compound 3 is solid state and stable in properties, is suitable as medicine intermediate and uses, prepare raw material 2-methyl-3-butyne-2-alcohol needed for compound 3 or other reagent all cheap and easy to get, thus, cost is low; Described reaction conditions is gentle, is suitable for suitability for industrialized production.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, mmol represents mmole, and h represents hour, and g represents gram, and ml represents milliliter, and Min represents minute.
The synthesis of embodiment 1 4-(imidazo [1,2-b] pyridazine-3-base)-2-methyl-3-butyne-2-alcohol
3-bromo imidazo [1,2, b] pyridazine (20.00g), CuI (1.92g), Pd (PPh
3)
4(5.83g), 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU) (18.45g) and 2-methyl-3-butyne-2-alcohol (12.74g) join in toluene (500mL) respectively.Be heated to 70 DEG C under reaction mixture nitrogen protection, reaction mixture is down to room temperature after stirring reaction 4h at 70 DEG C, passes through suction filtered through kieselguhr; diatomite layer toluene (3 × 50mL) washs; concentrating under reduced pressure, the enriched material silicagel column separation and purification obtained, eluent is: CH
2cl
2/ MeOH (V/V is 50/1), obtains 4-(imidazo [1,2-b] pyridazine-3-base)-2-methyl-3-butyne-2-alcohol, yellow solid (12.35g, yield: 58.96%).
1H NMR(600MHz,DMSO-d6)δ8.64(dd,J
1=1.5Hz,J
2=4.5,1H),8.18(d,J=9.0Hz,1H),8.02(s,1H),7.32(dd,J
1=4.2Hz,J
2=9.0,1H),5.64(s,1H),1.52(s,6H)。
The synthesis of embodiment 2 3-ethynyl imidazo [1,2-b] pyridazine
To 4-(imidazo [1, 2-b] pyridazine-3-base)-2-methyl-3-butyne-2-alcohol (9.37g) toluene solution (450mL) in add NaOH (7.45g), reaction mixture is after vacuum outgas nitrogen replacement three times, after reaction mixture nitrogen protection heating reflux reaction 22h, reaction mixture is cooled to room temperature, filtered by suction filtered through kieselguhr, diatomite layer toluene (3 × 50mL) washs, the enriched material silicagel column separation and purification that concentrating under reduced pressure filtrate obtains, eluent is ethyl acetate/hexanaphthene is 1:10 to 1:5, obtain 3-ethynyl imidazo [1, 2-b] the pure solid of pyridazine (4.58g) white needles, yield: 58.5%, HPLC purity 99.96%.
1H NMR(600MHz,DMSO-d6)δ8.64(dd,J
1=1.2Hz,J
2=4.2Hz,1H),8.20(dd,J
1=1.5Hz,J
2=9.3Hz,1H),8.11(s,1H),7.34(dd,J
1=4.5Hz,J
2=9.3Hz,1H),4.95(s,1H)。
The preparation of embodiment 3 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-(4-((4-methylpiperazine-1-yl)-methyl)-3-(trifluoromethyl) phenyl) benzamide
The iodo-4-methyl of 3--N-(4-((4-methylpiperazine-1-yl) methyl)-3-((trifluoromethyl) phenyl) benzoyl (15.74g), Pd (PPh is added successively in DMF (315ml)
3)
4(1.75g), CuI (0.41g), 3-ethynyl imidazo [1,2-b] pyridazine (9.58g) and DIPEA (7.87g), sealing, degassed 3 times of mixture vacuum nitrogen displacement, stirring at room temperature reaction under nitrogen protection.After reaction 24h, by reaction system by filter paper filtering, at filtrate is cooled to about 5 DEG C, slowly drip tap water (about 315g) wherein, a large amount of solid is had to separate out, after system moves to stirred at ambient temperature 2h, suction filtration, obtain title compound, khaki color solid, heavy 20.48g after drying.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (10)
1. prepare the method for 3-ethynyl imidazo [1,2-b] pyridazine (compound 2) for one kind,
It comprises, and in a solvent, 4-(imidazo [1,2-b] pyridazine-3-base)-2-methyl-3-butyne-2-alcohol (compound 3) mixes with alkali and reacts,
2. the method for claim 1, described alkali is alkalimetal hydride, alkaline earth metal hydride, alkali metal hydroxide, alkaline earth metal hydroxides or its combination.
3. method as claimed in claim 2, described alkali is sodium hydride, potassium hydride KH, hydrolith, sodium hydroxide, lithium hydroxide, potassium hydroxide or its combination.
4. the method for claim 1, the compound 3 relative to 1.0 moles, the consumption of described alkali is about 2.0 moles to about 6.0 moles, or is about 4.0 moles.
5. the method for claim 1, described solvent is benzene, toluene or dimethylbenzene or its combination, and the temperature of reaction of described reaction is about 40 degrees Celsius of reflux temperatures to reaction system.
6. for the preparation of a compound for the compound 2 shown in claim 1,4-(imidazo [1,2-b] pyridazine-3-base)-2-methyl-3-butyne-2-alcohol, its structure is such as formula shown in (3):
7. prepare a method for compound 3 described in claim 1, it comprises: obtained through Sonogashira linked reaction by compound 4 and 2-methyl-3-butyne-2-alcohol (compound 5),
Wherein, L is methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl or Cl, Br or I.
8. method as claimed in claim 7, described Sonogashira linked reaction is carried out in ether solvent, aromatic hydrocarbon solvent or ether solvent and the mixed solvent of water or the mixed solvent of aromatic hydrocarbon solvent and water, or described Sonogashira linked reaction is carried out in the mixed solvent of tetrahydrofuran (THF) and water, or described Sonogashira linked reaction is carried out in the mixed solvent of 2-methyltetrahydrofuran and water, or the solvent of described Sonogashira linked reaction is the mixed solvent of dimethylbenzene and water.
9. method as claimed in claim 7, described Sonogashira linked reaction can be carried out under base catalysis, described alkali is salt of wormwood, sodium carbonate, cesium carbonate, saleratus, sodium bicarbonate, potassiumphosphate, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene or diethylamine or its combination, compound 4 relative to 1 mole, the consumption of described alkali is about 2 moles to about 4.0 moles, or is about 3.0 moles.
10. method as claimed in claim 7, the temperature of reaction of described Sonogashira linked reaction is about 40 degrees Celsius to about 100 degrees Celsius, or is about 70 degrees Celsius to about 90 degrees Celsius.
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CN111004240A (en) * | 2019-12-13 | 2020-04-14 | 山东铂源药业有限公司 | Synthetic method of ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine |
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CN110372705A (en) * | 2019-08-05 | 2019-10-25 | 辽宁大学 | New substituted benzamide compound and its pharmaceutically acceptable salt and preparation method and application |
CN116444525A (en) * | 2023-03-27 | 2023-07-18 | 成都苑东生物制药股份有限公司 | Preparation method of ponatinib hydrochloride A crystal form |
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CA3022250A1 (en) * | 2012-12-12 | 2014-06-12 | Ariad Pharmaceuticals, Inc. | Crystalline forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-n-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride |
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CN111004240A (en) * | 2019-12-13 | 2020-04-14 | 山东铂源药业有限公司 | Synthetic method of ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine |
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