CN111004240B - Synthetic method of ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine - Google Patents
Synthetic method of ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine Download PDFInfo
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- CN111004240B CN111004240B CN201911279928.7A CN201911279928A CN111004240B CN 111004240 B CN111004240 B CN 111004240B CN 201911279928 A CN201911279928 A CN 201911279928A CN 111004240 B CN111004240 B CN 111004240B
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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
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a ponatinib intermediate 3-ethynylimidazo [1,2-b]A method for synthesizing pyridazine. The synthesis method adopts 3-pyridaben and 2-chloracetamate to synthesize a compound I under the alkaline conditionReacting with NBS to generate a compound II, reacting the compound II with sodium p-toluenesulfonate to generate an active esterified compound III, and finally introducing acetylene gas into the compound III in an aprotic solvent to react to obtain the 3-ethynylimidazo [1,2-b ]]Pyridazine. The method has simple operation steps, cheap and easily obtained raw materials, and is suitable for the large-scale production of generative enterprises.
Description
Technical Field
The invention relates to a synthetic method of a ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine, belonging to the technical field of organic synthesis.
Background
Ponatinib (ponatinib) is an oral multi-target tyrosine kinase inhibitor developed by Ariad in the United states, can effectively inhibit the activities of Bcr-Ab1 (including T315I mutation), Flt-3 and Scr kinase, and is mainly used for treating Chronic Myelogenous Leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). The structural formula of the ponatinib is shown as follows.
3-ethynylimidazo [1,2-b ] pyridazine is a key intermediate in the synthesis of ponatinib. Tiankun et al disclose a synthetic method of the above-mentioned intermediate (Tiankun, Yueyanliang, Zhongchang Ling, etc.. Ponatinib synthesis [ J ]. Guangdong chemical, 2013, 12(40), 24-25), the synthetic method uses imidazo [1,2-b ] pyridazine as a starting material, bromizes, then reacts with trimethylsilyl acetylene under the catalysis of catalysts (cuprous iodide and bis (triphenylphosphine benzene) palladium), and finally removes trimethylsilyl with tetrabutylammonium fluoride to obtain 3-acetylenic imidazo [1,2-b ] pyrazine, the synthetic route is shown below.
Tangwu et al disclose a 3-acetylenic imidazo [1,2-b]The synthetic route of pyrazine is similar to that described above. It is imidazo [1,2-b ]]The pyridazine is taken as a raw material, and is subjected to iodination reaction with N-iodosuccinimide in trifluoroacetic acid/dichloromethane at room temperature to prepare 3-iodoimidazo [1,2-b ]]Pyridazine; with trimethylsilyl acetylene in Pd (OAc)2Preparing 3-trimethylsilylethynyl imidazo [1,2-b ] by Heck reaction under catalysis]Pyridazine, and then removing trimethylsilyl group under the action of potassium carbonate to obtain 3-ethynylimidazo [1,2-b]Pyridazine (Tangwu, Wangpeng Xue, Jinbo, etc.. 3-alkynyl imidazo [1,2-b ]]Simple Synthesis of pyridazine [ J]Synthetic chemistry, 2016 stage 7, 643-646).
The Heck reaction processes of the two synthesis methods both use a noble metal palladium catalyst and an expensive reagent, namely trimethylsilyl acetylene, and are not suitable for industrial mass production. Meanwhile, the initial raw material imidazo [1,2-b ] pyridazine is synthesized by using 3-pyridazinone and 2-chloroacetaldehyde as raw materials in the traditional method, and the 2-chloroacetaldehyde is a toxic substance and has great harm to human bodies.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a synthetic method of a ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine. The synthesis method comprises the steps of synthesizing a compound I by using 3-pyridinone and 2-chloroacetamide under an alkaline condition, reacting the compound I with NBS to generate a compound II, reacting the compound II with sodium p-toluenesulfonate to generate an active esterified substance III, and finally introducing acetylene gas into the compound III in an aprotic solvent to react to obtain the 3-ethynylimidazo [1,2-b ] pyridazine. The method has simple operation steps, cheap and easily obtained raw materials, and is suitable for the large-scale production of generative enterprises.
The technical scheme of the invention is as follows: a synthetic method of a ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine is characterized in that,
1) under the alkaline condition, reacting 3-pyridazinone with 2-chloroethylamine or 2-chloroethylamine hydrochloride to obtain a compound I;
2) reacting the compound I with a halogenated reagent to obtain a compound II;
3) reacting the compound II with sodium p-toluenesulfonate to obtain a compound III;
4) dissolving the compound III in an aprotic solvent in a closed pressure vessel, and introducing acetylene gas under an alkaline condition to react to generate 3-ethynylimidazo [1,2-b ] pyridazine.
The synthetic route is as follows:
the base used in step 1) may be organic base such as triethylamine, N-diisopropylethylamine and the like, and the reaction solvent may be aprotic solvent such as dichloromethane, dichloroethane, chloroform, toluene and the like, preferably chloroform. In the step 1), the reaction temperature is-5-100 ℃, and preferably 50-70 ℃.
The halogenating agent in the step 2) can be NBS (N-bromosuccinimide), NIS (N-iodosuccinimide), NCS (N-bromosuccinimide) and bromine, and the invention prefers NBS. The reaction temperature in the step 2) is preferably 35-50 ℃. Further, adding an initiator azobisisobutyronitrile in the step 2) for initiation.
The reaction solvent used in step 3) can be selected from strong polar aprotic solvents, such as DMF, DMSO, tetrahydrofuran, acetonitrile, and the like, DMSO is preferred, the reaction temperature can be 0-200 ℃, and 100-150 ℃ is preferred. In step 3), potassium iodide is preferably added as a catalyst.
In step 4), the reaction solvent used can be all aprotic solvents, DMF is preferred in the invention, and the base used is inorganic base, and can be potassium carbonate, sodium carbonate, cesium carbonate and the like, and potassium carbonate is preferred. The temperature is 0-100 ℃, the pressure used for reaction is 0-0.6 Mpa, the preferable temperature is 20-50 ℃, and the pressure used for reaction is 0.2-0.4 Mpa.
Further, the method comprises the following specific steps:
1) adding 3-pyridazinone into a reaction solvent, adding 2-chloroethylamine hydrochloride and triethylamine, and reacting at 50-70 ℃ under an anhydrous condition; after the 3-pyridazinone completely reacts, cooling to room temperature, adding water, stirring, standing for layering, and directly entering the next reaction after an organic layer is dried;
2) adding initiators of azobisisobutyronitrile and NBS into the reaction liquid obtained in the step 1), controlling the temperature to be 30-50 ℃, stirring for reaction, adding a sodium bisulfite solution to crack redundant NBS, cooling, carrying out suction filtration on a precipitated product, and drying to obtain a compound II;
3) adding a compound II, sodium p-toluenesulfonate and a catalyst potassium iodide into a reaction solvent, heating to 100-150 ℃ for reaction, cooling reaction liquid after the reaction is finished, pouring the reaction liquid into water to separate out a product, performing suction filtration and drying to obtain a compound III;
4) adding a compound III into an autoclave, adding a reaction solvent and potassium carbonate, and introducing acetylene gas to react at the temperature of 20-50 ℃ and the pressure of 0.2-0.4 Mpa; and after the reaction is finished, removing unreacted potassium carbonate by suction filtration, pouring the feed liquid into water to separate out a solid, and obtaining the 3-ethynylimidazo [1,2-b ] pyridazine by suction filtration and drying.
Preferably, the step 4) is replaced by nitrogen before and after the acetylene gas is introduced.
In the step 1), the molar ratio of the 3-pyridazinone to the 2-chloroethylamine hydrochloride to the triethylamine is 1: 1.0-1.5: 2.0 to 2.5.
In the step 2), the molar ratio of the 3-pyridazinone to the NBS is 1: 1.0 to 1.1.
In the step 3), the molar ratio of the compound II to the sodium p-toluenesulfonate is 1: 1.0 to 2.0.
In the step 4), the molar ratio of the compound III to the potassium carbonate is 1: 1.0 to 2.0.
The invention has the beneficial effects that:
1. in the synthesis process of imidazo [1,2-b ] pyridazine, 2-chloroethylamine hydrochloride is used for replacing a toxic substance 2-chloroacetaldehyde in the traditional method to reduce the harm to human bodies;
2. the method has the advantages of simple operation steps, cheap and easily-obtained raw materials and high product yield by adopting the active ester method to replace the Heck reaction in the traditional method, and is more suitable for the large-scale production of generative enterprises.
Detailed Description
Example 1:
1) placing 936g of 3-pyridazinone and 900g of chloroform in a 2L reaction bottle, adding 122g of 2-chloroethylamine hydrochloride and 222g of triethylamine, adding 10g of anhydrous sodium sulfate, stirring at 20-25 ℃ for 1 hour, heating to 60 ℃, carrying out reflux reaction for 4 hours, detecting that all the 3-pyridazinone is reacted by TLC (EA: PE (1: 3)), cooling to 20-25 ℃, adding 200g of water, stirring for 1 hour, standing for layering, drying a chloroform layer for 3 hours by using 20g of anhydrous magnesium sulfate, carrying out suction filtration, and directly feeding a mother solution to the next reaction.
2) Adding 2g of azobisisobutyronitrile into the reaction solution obtained in the previous step, adding 187g of NBS in batches, carrying out light-shielding reaction, controlling the temperature to be 40-45 ℃ after the addition, stirring for 5-6 hours, separating out a large amount of solid, adding the prepared 10% sodium bisulfite solution into a reaction bottle, stirring for 30 minutes (cracking redundant NBS), cooling to-5 ℃ for suction filtration to obtain brown solid, drying at 50 ℃ to obtain 176g of a compound II product, wherein the yield is 89%, and the mother solution can be recovered and reused after layered treatment.
3) Putting 99g of compound II and 400ml of DMF (dimethyl formamide) into a 1000ml reaction bottle, adding 147g of sodium p-toluenesulfonate, adding 1g of potassium iodide, heating to 120 ℃ for reaction for 12 hours, cooling the reaction liquid to 60 ℃, pouring into 3000ml of water to precipitate a large amount of solid, performing suction filtration, and drying at 50-55 ℃ to obtain 115.8g of compound III, wherein the yield is 80%.
4) Adding 100g of compound III into an autoclave, adding 600g of DMF, adding 71g of potassium carbonate, introducing acetylene gas to increase the pressure to 0.2Mpa after nitrogen replacement, keeping the reaction for 3 hours at the temperature of 40-45 ℃ until the pressure of a pressure gauge is not reduced, after the reaction is finished, replacing the nitrogen gas, pumping the material out, removing unreacted potassium carbonate by suction filtration, pouring into 3000ml of water to precipitate a large amount of yellow solid, and performing suction filtration and drying to obtain 40.0g of a product with the yield of 79%.
Example 2:
adding 100g of compound III into an autoclave, adding 600g of DMF, adding 71g of potassium carbonate, performing nitrogen replacement, introducing acetylene gas to increase the pressure to 0.4Mpa, reacting at room temperature of 20-25 ℃ until the pressure of a pressure gauge is not reduced, maintaining the reaction for 3 hours, performing nitrogen replacement after the reaction is finished, pumping out the material, performing suction filtration to remove unreacted potassium carbonate, recovering DMF to about 80%, adding 1000ml of water to the residue, stirring for half an hour, performing suction filtration and drying to obtain 41.0g of a product, wherein the yield is 82%.
Claims (10)
1. A synthetic method of a ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine is characterized by comprising the following steps:
1) under the alkaline condition, reacting 3-pyridazinone with 2-chloroethylamine or 2-chloroethylamine hydrochloride to obtain a compound I;
2) reacting the compound I with a halogenated reagent to obtain a compound II;
3) reacting the compound II with sodium p-toluenesulfonate to obtain a compound III;
4) dissolving a compound III in an aprotic solvent in a closed pressure vessel, and introducing acetylene gas under an alkaline condition to react to generate 3-ethynylimidazo [1,2-b ] pyridazine;
wherein the compound I is imidazo [1,2-b ] pyridazine;
the compound II is
X is halogen;
the compound III is
2. The method for synthesizing ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine of claim 1, wherein the base used in step 1) is triethylamine or N, N-diisopropylethylamine; the reaction solvent is dichloromethane, dichloroethane, chloroform or toluene.
3. The method for synthesizing ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine according to claim 1, wherein the reaction temperature in step 1) is 50-70 ℃.
4. The method for synthesizing ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine of claim 1, wherein the halogenating agent in step 2) is N-bromosuccinimide, N-iodosuccinimide or bromine.
5. The method for synthesizing ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine according to claim 1, wherein the reaction temperature in step 2) is 35-50 ℃, and an initiator azobisisobutyronitrile is added for initiation.
6. The method for synthesizing ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine of claim 1, wherein the reaction solvent used in step 3) is DMF, DMSO, tetrahydrofuran or acetonitrile.
7. The method for synthesizing ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine of claim 1, wherein the reaction temperature in step 3) is 100-150 ℃, and potassium iodide is added as a catalyst.
8. The method for synthesizing pinatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine according to claim 1, characterized in that in the step 4), the base used is potassium carbonate, sodium carbonate or cesium carbonate; the reaction temperature is 20-50 ℃, and the reaction pressure is 0.2-0.4 Mpa.
9. The method for synthesizing pennatatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine according to any one of claims 1-8,
1) adding 3-pyridazinone into a reaction solvent, adding 2-chloroethylamine hydrochloride and triethylamine, and reacting at 50-70 ℃ under an anhydrous condition; after the 3-pyridazinone completely reacts, cooling to room temperature, adding water, stirring, standing for layering, and directly entering the next reaction after an organic layer is dried;
2) adding initiators of azobisisobutyronitrile and N-bromosuccinimide into the reaction liquid obtained in the step 1), controlling the temperature to be 35-50 ℃, stirring for reaction, adding a sodium bisulfite solution to crack redundant N-bromosuccinimide, cooling, carrying out suction filtration on a precipitated product, and drying to obtain a compound II;
3) adding a compound II, sodium p-toluenesulfonate and a catalyst potassium iodide into a reaction solvent, heating to 100-150 ℃ for reaction, cooling reaction liquid after the reaction is finished, pouring the reaction liquid into water to separate out a product, performing suction filtration and drying to obtain a compound III;
4) adding a compound III into an autoclave, adding an aprotic solvent and potassium carbonate, and introducing acetylene gas to react at the temperature of 20-50 ℃ and the pressure of 0.2-0.4 Mpa; and after the reaction is finished, removing unreacted potassium carbonate by suction filtration, pouring the feed liquid into water to separate out a solid, and obtaining the 3-ethynylimidazo [1,2-b ] pyridazine by suction filtration and drying.
10. The method for synthesizing ponatinib intermediate 3-ethynylimidazo [1,2-b ] pyridazine of claim 9, wherein step 4) is performed by nitrogen substitution before and after the acetylene gas is introduced.
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| ES2403206T3 (en) * | 2005-12-23 | 2013-05-16 | Ariad Pharmaceuticals, Inc. | Heteroaryl bicyclic compounds |
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| CA2815506C (en) * | 2012-12-12 | 2018-12-11 | 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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