CN113354573B - Method for large-scale production of alpha, alpha-terpyridine - Google Patents
Method for large-scale production of alpha, alpha-terpyridine Download PDFInfo
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- CN113354573B CN113354573B CN202110732345.6A CN202110732345A CN113354573B CN 113354573 B CN113354573 B CN 113354573B CN 202110732345 A CN202110732345 A CN 202110732345A CN 113354573 B CN113354573 B CN 113354573B
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
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Abstract
The invention discloses a method for producing alpha, alpha-terpyridine in large scale,the following synthetic route is adopted:
Description
Technical Field
The invention relates to a method for producing alpha, alpha-terpyridine on a large scale, belonging to the technical field of organic synthesis.
Background
The CAS number of the alpha, alpha-terpyridine is 1148-79-4, and the chemical structural formula is shown as follows:
terpyridines were first isolated from Morgan and Burstall in the 30 s of the 20 th century. Because the terpyridine and the derivatives thereof have R electron donating capability and P electron accepting capability, the terpyridine and the derivatives thereof can form stable complexes with various metal ions, and are chelate ligands which are widely applied in modern coordination chemistry, and because the terpyridine complexes have good affinity with N and S-containing biological macromolecules such as protein and DNA, and the luminescent property can be changed, the terpyridine and the derivatives thereof can be applied to biological probes; in addition, because the alpha, alpha-terpyridine contains three N atoms, and can be used as a tridentate ligand to chelate with various transition metals and form stable complexes, the terpyridine is widely applied to supermolecular chemistry, chemists have successfully synthesized functional complexes with novel ladder-shaped, lattice-shaped, spiral-shaped, catenated, knot-shaped and dendritic structures by utilizing the unique structure of the terpyridine, and the functional complexes are applied to the fields of antitumor drugs, optical materials, molecular catalysis, solar energy conversion and the like, for example, the terpyridine complex is used for designing a light-emitting device in photochemistry or is used as a photosensitizer in photoelectric conversion. Namely, terpyridine has wide application prospect and huge potential development value.
The existing method for synthesizing terpyridine is mainly a coupling method, and the coupling method needs a tin reagent, has high toxicity, needs a palladium catalyst, has the problems of high cost, complex post-treatment, difficult removal of metal residue and the like, and is not suitable for large-scale production. Chinese patent document CN109096339A discloses a process for synthesizing an intermediate 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one by using 2-acetylpyridine and N, N-dimethylformamide dimethyl acetal, and then synthesizing terpyridine by using the intermediate and 2-acetylpyridine in the presence of potassium tert-butoxide, wherein although the process is carried out in two steps, a noble metal catalyst is not needed, the xylene is removed by reduced pressure distillation in the first step of reaction, and the problems of environmental protection and energy consumption exist; and the second step reaction needs to be purified by flash column chromatography, so that the yield is only 15%; therefore, the method is not suitable for the requirement of large-scale production.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a method for producing α, α, α -terpyridine in large scale.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for producing alpha, alpha-terpyridine in large scale adopts the following synthetic route:
wherein the reaction operation of the step a is as follows:
adding 2-acetylpyridine, N-dimethylformamide dimethyl acetal and a catalyst into an organic solvent at room temperature, reacting under reflux, cooling a reaction solution to room temperature after the reaction is finished, pouring the reaction solution into a sodium hydroxide aqueous solution, extracting a product by using dichloromethane, washing, drying and concentrating an obtained organic phase, and recrystallizing an obtained crude product to obtain an intermediate: 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one.
In a preferred embodiment, the catalyst is selected from at least one of guanylthiourea, piperazine-1-formamidine, guanidinoacetic acid, D-arginine hydrochloride, L-arginine hydrochloride, creatine monohydrate, guanylurea sulfate, tetramethylguanidine, and 3-guanidino-L-alanine hydrochloride.
In a further preferred embodiment, the catalyst is selected from guanylurea sulfate.
In a preferred embodiment, the organic solvent is at least one selected from tetrahydrofuran, acetonitrile, toluene, xylene, ethanol, isopropanol, tert-butanol, chloroform, and dioxane.
Further preferably, the organic solvent is selected from tetrahydrofuran, toluene or chloroform.
In a preferred embodiment, the recrystallization solvent is at least one selected from the group consisting of water, methanol, isopropanol, ethanol, ethyl acetate, dichloromethane, petroleum ether, n-heptane, n-hexane, and methyl-t-butyl ether.
In a further preferred embodiment, the recrystallization solvent is petroleum ether.
In one embodiment, the reaction of step b is operated as follows:
at room temperature, sequentially adding anhydrous tetrahydrofuran, potassium tert-butoxide and 2-acetylpyridine into a reaction kettle, stirring and reacting for 2-4 hours at room temperature, and then adding an intermediate: adding 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone into a reaction kettle, continuously stirring at room temperature for reacting for 16-20 hours, adding ammonium acetate and acetic acid into a reaction system, performing reflux reaction for 4-6 hours, then performing reduced pressure concentration, dissolving the concentrated residue with dichloromethane to obtain an organic phase, washing, drying and concentrating the obtained organic phase, and finally recrystallizing the obtained product to obtain the pure alpha, alpha-terpyridine.
In a preferred scheme, the ratio of the used volume of the anhydrous tetrahydrofuran to the feeding mass of the 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone is (5-15): 1.
in a further preferred embodiment, the ratio of the used volume of the anhydrous tetrahydrofuran to the fed mass of the 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is 10:1.
in a preferred embodiment, the molar ratio of ammonium acetate to 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is (2-5): 1.
in a further preferred embodiment, the molar ratio of ammonium acetate to 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is 5:1.
in a preferable embodiment, the solvent for recrystallizing the product is at least one selected from the group consisting of water, methanol, isopropanol, ethanol, ethyl acetate, dichloromethane, petroleum ether, n-heptane, n-hexane, and methyl-t-butyl ether.
In a further preferred embodiment, the solvent used for recrystallizing the product is n-heptane.
Compared with the prior art, the invention has the following remarkable beneficial effects:
the experiment shows that: the method has mild reaction conditions, simple operation, lower requirement on equipment and easy purification treatment, and can obtain the target product with the HPLC purity of 99.4 percent only by simple recrystallization treatment, in particular, the method can break through the existing small production bottleneck, easily realize the production scale from kilogram to hundred kilogram, has high yield, and the total yield of two steps can reach 68.4 percent, so that the production cost can be reduced by at least 40 percent compared with the prior art; therefore, compared with the prior art, the method provided by the invention has significant progress, and has significant economic value for realizing large-scale production of the alpha, alpha-terpyridine.
Detailed Description
The technical solution of the present invention is further described in detail and fully below with reference to specific embodiments.
The method for producing the alpha, alpha-terpyridine in a large scale, which is provided by the following embodiment, adopts the following synthetic route:
example 1: preparation of intermediate 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one
Adding 94L of tetrahydrofuran into a high-low temperature jacket reaction kettle at room temperature, then sequentially adding 2-acetylpyridine (9.4kg, 1.0eq), N-dimethylformamide dimethylacetal (11.2kg, 1.20eq) and guanyl thiourea (920g, 0.10eq), heating to reflux reaction, monitoring the reaction process by TLC, when the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into 20L of 40% sodium hydroxide solution, then extracting twice by using 50L of dichloromethane, combining organic phases, washing the obtained organic phases by using saturated common salt water, drying by using anhydrous sodium sulfate, concentrating, recrystallizing the obtained crude product by using petroleum ether to obtain 5.77kg of an intermediate: 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one in 42.0% molar yield.
Example 2: preparation of intermediate 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one
Adding 94L of tetrahydrofuran into a high-low temperature jacket reaction kettle at room temperature, then sequentially adding 2-acetylpyridine (9.4kg, 1.0eq), N-dimethylformamide dimethylacetal (11.2kg, 1.20eq) and tetramethylguanidine (900g, 0.10eq), heating to reflux reaction, monitoring the reaction process by TLC, cooling the reaction liquid to room temperature, pouring the reaction liquid into 20L of 40% sodium hydroxide aqueous solution, then extracting twice by using 50L of dichloromethane, combining organic phases, washing the obtained organic phases by using saturated common salt water, drying by using anhydrous sodium sulfate, concentrating, recrystallizing the obtained crude product by using petroleum ether to obtain 6.65kg of intermediate: 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one in 48.4% molar yield.
Example 3: preparation of intermediate 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one
Adding 94L of tetrahydrofuran into a high-low temperature jacket reaction kettle at room temperature, then sequentially adding 2-acetylpyridine (9.4kg, 1.0eq), N-dimethylformamide dimethyl acetal (11.2kg, 1.20eq) and 3-guanidino-L-alanine hydrochloride (1.42kg, 0.10eq), heating to reflux reaction, monitoring the reaction process by TLC, pouring the reaction liquid into 20L of 40% sodium hydroxide aqueous solution after the reaction is finished and cooled to room temperature, then extracting twice by 50L of dichloromethane, combining organic phases, washing the obtained organic phase by using saturated saline, drying by using anhydrous sodium sulfate, concentrating, recrystallizing the obtained crude product by using petroleum ether, and obtaining 4.65kg of an intermediate: 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one in 33.9% molar yield.
Example 4: preparation of intermediate 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one
Adding 94L of tetrahydrofuran into a high-low temperature jacket reaction kettle at room temperature, then sequentially adding 2-acetylpyridine (9.4kg, 1.0eq), N-dimethylformamide dimethyl acetal (11.2kg, 1.20eq) and guanylurea sulfate (1.84kg, 0.10eq), heating to reflux reaction, monitoring the reaction process by TLC, when the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into 20L of 40% aqueous solution of sodium hydroxide, then extracting twice by using 50L of dichloromethane, combining organic phases, washing the obtained organic phases by using saturated saline water, drying by using anhydrous sodium sulfate, concentrating, recrystallizing the obtained crude product by using petroleum ether, and obtaining 7.25kg of an intermediate: 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one in 52.8% molar yield.
Example 5: preparation of intermediate 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one
Adding 94L of toluene into a high-low temperature jacketed reaction kettle at room temperature, then sequentially adding 2-acetylpyridine (9.4kg, 1.0eq), N-dimethylformamide dimethyl acetal (11.2kg, 1.20eq) and guanylurea sulfate (1.84kg, 0.10eq), heating to reflux reaction, monitoring the reaction process by TLC, when the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into 20L of sodium hydroxide aqueous solution with the concentration of 40%, then extracting twice by using 50L of dichloromethane, combining organic phases, washing the obtained organic phases by using saturated saline water, drying by using anhydrous sodium sulfate, concentrating, recrystallizing the obtained crude product by using petroleum ether, and obtaining 10.3kg of an intermediate: 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one in 75.0% molar yield.
Example 6: preparation of intermediate 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one
At room temperature, 94L of chloroform is added into a high-low temperature jacket reaction kettle, then 2-acetylpyridine (9.4kg, 1.0eq), N-dimethylformamide dimethyl acetal (11.2kg, 1.20eq) and guanylurea sulfate (1.84kg, 0.10eq) are sequentially added, the temperature is raised to reflux reaction, the reaction process is monitored by TLC, when the reaction is finished, the reaction liquid is cooled to room temperature, then the reaction liquid is poured into 20L of 40% sodium hydroxide solution, then 50L of dichloromethane is used for extraction twice, organic phases are combined, the obtained organic phases are washed by saturated common salt water and dried by anhydrous sodium sulfate for concentration, and the obtained crude product is recrystallized by petroleum ether to obtain 12.25kg of intermediate: 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one in a molar yield of 89.2%.
Example 7: preparation of target alpha, alpha-terpyridine
At room temperature, 82.5L of anhydrous tetrahydrofuran, potassium tert-butoxide (7.0kg, 2.0eq) and 2-acetylpyridine (3.77kg, 1.0eq) are sequentially added into a high-low temperature jacket reaction kettle, the mixture is stirred at room temperature for reaction for 3 hours, and the reaction progress is monitored by TLC; the intermediate is then: adding 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone (5.5 kg, 1.0eq) into a reaction kettle, and continuously reacting at room temperature for 18h after the addition is finished; then adding ammonium acetate (4.8kg, 2.0eq) and 55L acetic acid into the reaction system, and making reflux reaction for 5h; concentrating under reduced pressure, dissolving the concentrated residue with 50L dichloromethane to obtain an organic phase, washing the obtained organic phase with water, drying with anhydrous sodium sulfate, concentrating, and recrystallizing the obtained product with n-heptane to obtain pure product of alpha, alpha-terpyridine, wherein the molar yield is 45.9% and the HPLC purity is 99.2%.
1H NMR(400MHz,Chloroform-d)δ8.71-8.70(ddt,J＝4.8,1.6,0.7Hz,2H),8.63-8.61(dd,J＝7.9,1.2Hz,2H),8.46-8.44(d,J＝7.8Hz,2H),7.98-7.95(t,J＝7.8Hz,1H),7.89-7.84(td,J＝7.7,1.8Hz,2H),7.35-7.32(ddd,J＝7.5,4.8,1.2Hz,2H).
Example 8: preparation of target alpha, alpha-terpyridine
At room temperature, 55L of anhydrous tetrahydrofuran, potassium tert-butoxide (7.0kg, 2.0eq) and 2-acetylpyridine (3.77kg, 1.0eq) are sequentially added into a high-low temperature jacket reaction kettle, and the mixture is stirred and reacted for 3 hours at room temperature, and the reaction progress is monitored by TLC; the intermediate is then: adding 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone (5.5 kg,1.0 eq) into a reaction kettle, and continuously reacting at room temperature for 18h after the addition is finished; adding ammonium acetate (4.8kg, 2.0eq) and 55L acetic acid into the reaction system, and making reflux reaction for 5h; concentrating under reduced pressure, dissolving the concentrated residue with 50L dichloromethane to obtain an organic phase, washing the obtained organic phase with water, drying with anhydrous sodium sulfate, concentrating, and recrystallizing the obtained product with n-heptane to obtain pure alpha, alpha-terpyridine product 3.4kg, with molar yield of 46.7% and HPLC purity of 99.4%.
Example 9: preparation of target alpha, alpha-terpyridine
At room temperature, adding 27.5L of anhydrous tetrahydrofuran, potassium tert-butoxide (7.0kg, 2.0eq) and 2-acetylpyridine (3.77kg, 1.0eq) in sequence into a high-low temperature jacket reaction kettle, stirring at room temperature for reaction for 3 hours, and monitoring the reaction progress through TLC; the intermediate: adding 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone (5.5 kg, 1.0eq) into a reaction kettle, and continuously reacting at room temperature for 18h after the addition is finished; then adding ammonium acetate (4.8kg, 2.0eq) and 55L acetic acid into the reaction system, and making reflux reaction for 5h; concentrating under reduced pressure, dissolving the concentrated residue with 50L dichloromethane to obtain an organic phase, washing the obtained organic phase with water, drying with anhydrous sodium sulfate, concentrating, and recrystallizing the obtained product with n-heptane to obtain 2.8kg of pure alpha, alpha-terpyridine product with molar yield of 38.5% and HPLC purity of 99.0%.
Example 10: preparation of target alpha, alpha-terpyridine
At room temperature, 55L of anhydrous tetrahydrofuran, potassium tert-butoxide (7.0kg, 2.0eq) and 2-acetylpyridine (3.77kg, 1.0eq) are sequentially added into a high-low temperature jacket reaction kettle, and the mixture is stirred and reacted for 3 hours at room temperature, and the reaction progress is monitored by TLC; the intermediate is then: adding 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone (5.5 kg, 1.0eq) into a reaction kettle, and continuously reacting at room temperature for 18h after the addition is finished; then adding ammonium acetate (10.5kg, 5.0 eq) and 55L acetic acid into the reaction system, and carrying out reflux reaction for 5h; concentrating under reduced pressure, dissolving the concentrated residue with 50L dichloromethane to obtain an organic phase, washing the obtained organic phase with water, drying with anhydrous sodium sulfate, concentrating, and recrystallizing the obtained product with n-heptane to obtain 5.57kg of pure alpha, alpha-terpyridine product with a molar yield of 76.7% and an HPLC purity of 99.4%.
Finally, it should be pointed out here that: the above are only some of the preferred embodiments of the present invention, and should not be construed as limiting the scope of the present invention, and the insubstantial modifications and adaptations made by those skilled in the art based on the above description of the present invention are within the scope of the present invention.
Claims (3)
1. A method for producing alpha, alpha-terpyridine in large scale adopts the following synthetic route:
the method is characterized in that the reaction operation of the step a is as follows:
adding 2-acetylpyridine, N-dimethylformamide dimethyl acetal and guanylurea sulfate into toluene or chloroform at room temperature, reacting under reflux, cooling the reaction liquid to room temperature after the reaction is finished, pouring the reaction liquid into a sodium hydroxide aqueous solution, extracting the product by using dichloromethane, washing the obtained organic phase, drying, concentrating, and recrystallizing the obtained crude product to obtain an intermediate: 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one;
the reaction operation of step b is as follows:
at room temperature, sequentially adding anhydrous tetrahydrofuran, potassium tert-butoxide and 2-acetylpyridine into a reaction kettle, stirring and reacting for 2-4 hours at room temperature, and then adding an intermediate: adding 1- (3-pyridyl) -3- (dimethylamino) -2-propylene-1-ketone into a reaction kettle, continuously stirring and reacting for 16-20 hours at room temperature, adding ammonium acetate and acetic acid into a reaction system, performing reflux reaction for 4-6 hours, then performing reduced pressure concentration, dissolving a concentrated residue with dichloromethane to obtain an organic phase, washing, drying and concentrating the obtained organic phase, and finally recrystallizing the obtained product to obtain an alpha, alpha-terpyridine pure product; wherein: the ratio of the used volume of the anhydrous tetrahydrofuran to the feeding mass of the 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is 10:1; the molar ratio of ammonium acetate to 1- (3-pyridyl) -3- (dimethylamino) -2-propen-1-one is 5:1.
2. the method of claim 1, wherein: step a, recrystallizing the crude product by using petroleum ether.
3. The process of claim 1, wherein step b recrystallizes the product from n-heptane.
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| CN109503562A (en) * | 2018-12-26 | 2019-03-22 | 西华大学 | 2- [4- (2- thienyl)] pyrimidine radicals urea derivative and its preparation method and application |
| WO2020060451A1 (en) * | 2018-09-17 | 2020-03-26 | Totalförsvarets Forskningsinstitut | Synthesis of ammonium dinitramide (adn) |
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| JP2019026619A (en) * | 2017-08-03 | 2019-02-21 | 国立大学法人山形大学 | Terpyridine derivative and organic electronic element using the same |
| CN109096339B (en) * | 2018-07-20 | 2020-10-02 | 云南大学 | Preparation of terpyridyl ruthenium complex and application of terpyridyl ruthenium complex in reverse transcriptase inhibition |
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| WO2020060451A1 (en) * | 2018-09-17 | 2020-03-26 | Totalförsvarets Forskningsinstitut | Synthesis of ammonium dinitramide (adn) |
| CN109503562A (en) * | 2018-12-26 | 2019-03-22 | 西华大学 | 2- [4- (2- thienyl)] pyrimidine radicals urea derivative and its preparation method and application |
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