CN109705013B - 1- (4-methylbenzyl) -3-amino-4-methylselenylmaleimide compound and preparation method thereof - Google Patents
1- (4-methylbenzyl) -3-amino-4-methylselenylmaleimide compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a 1- (4-methylbenzyl) -3-amino-4-methylseleno maleimide compound and a preparation method thereof, wherein dimethyl diselenide, N- (4-methylbenzyl) maleimide and morpholine are used as reaction raw materials in an organic solvent under the condition of oxygen, and carbon-carbon double bonds of the maleimide are subjected to oxidation coupling reaction simultaneously through transition metal copper catalyzed cascade reaction to obtain the 1- (4-methylbenzyl) -3-morphilinyl-4-methylseleno maleimide compound. The method has simple reaction conditions and high yield and purity of the product, develops a new synthetic route and method for preparing the 3-amino-4-methylselenobeimide compound, and has good application potential and research value.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a 1- (4-methylbenzyl) -3-amino-4-methylselenylmaleimide compound and a preparation method thereof.
Background
Maleimide as an important amide compound is widely present in natural products, bioactive molecules and clinical drug molecules, and a parent structure can be used for preparing derivatives such as succinimide, pyrrolidine and lactimide through various conversion reactions, so that how to efficiently and greenly synthesize the derivatives with maleimide skeletons is a target pursued by organic chemists based on the application of maleimide compounds in different fields. For example: the Pianxing professor of Zhongshan university utilizes an organic Base catalyst, takes 1, 4-dithio-2, 5-diol and maleimide as substrates, and prepares a chiral heterocyclic compound with a Tetrahydrothiophene skeleton structure (Diastereoscopic Synthesis of Biheterocyclic Tetrahydrothiophene derivative via Base-Catalyzed Cascade dye-Alder [3+2] cyclization reaction through Diastereoselective tandem Michael-Alder [3+2] cyclization reaction, wherein the compound has good biological and pharmaceutical activities through pharmacological activity research; in 2008, A.Yu.Simonov et al reported that (Synthesis of 4_ substistuted 3- [3- (bivalent amino methyl) indole-1-yl ] maleimides and study of the ability to inhibit the activity of the protein kinase C alpha, preservation of multiple drug resistance of tumor cells and cytoxicity, Russ.chem.Bull.2008, 57, 2011-2020), the use of 3-amino-4-arylmercaptomaleimide could inhibit protein kinase, prevent the development of tumor cell resistance and cytotoxicity.
As the compounds containing maleimide structure are so important, much research has been carried out on the synthesis thereof, however, there is only one example of reports on the synthesis of seleno-Maleimides, in 2017, Mahidun Baidiya et al, college of Ind. reports (Ru (II) -Catalyzed C-H catalysis on Maleimides with electrophoiles: A purification of Umpolling Strategy, org. Lett., 2017, 19, 1902-1905) on the synthesis of 3-seleno-Maleimides using expensive ruthenium-Catalyzed maleimide and diaryldiselenide, as follows:
although the prior art can solve the selenylation reaction of maleimide, the alkylselenisation reaction of maleimide and the bifunctional reaction of carbon-carbon double bonds in a diselenide-participated maleimide structure are not reported so far. Therefore, the method is particularly important for preparing the 3-amino-4-alkylseleno maleimide compound from raw materials which are simple and easy to process and have cheap and easily-obtained substrates, particularly for synthesizing the 1- (4-methylbenzyl) -3-morphinyl-4-methylseleno maleimide compound by utilizing the three-component tandem reaction of dimethyl diselenide, N- (4-methylbenzyl) maleimide and morpholine, and the need of continuing research and exploration still exists, which is the basis and the power for completing the method.
Disclosure of Invention
The technical problem to be solved by the invention is the problem of a synthetic route of the preparation method of the 1- (4-methylbenzyl) -3-morphininyl-4-methylseleno maleimide compound.
In order to solve the technical problems, the invention provides the following technical scheme:
in an organic solvent, under the condition of oxygen, dimethyl diselenide, N- (4-methylbenzyl) maleimide and morpholine are used as reaction raw materials, and carbon-carbon double bonds of the maleimide are subjected to oxidation coupling reaction simultaneously through transition metal copper catalyzed cascade reaction to obtain the 1- (4-methylbenzyl) -3-morphininyl-4-methylseleno maleimide compound.
The above reaction process can be represented by the following reaction formula:
the molar ratio of the dimethyl diselenide with the structure shown in the formula (I), the N- (4-methylbenzyl) maleimide with the structure shown in the formula (II) and the morpholine with the structure shown in the formula (III) is 4: 2: 3.
(1) Transition metal catalyst copper
The transition metal catalyst copper in the invention is cupric acetate, cupric chloride, cupric bromide or cuprous iodide, preferably cupric acetate, and the dosage ratio of cupric acetate to the formula (II) is 0.1: 1-0.3: 1, preferably 0.1 in terms of molar weight.
(2) Organic solvent
The reaction solvent in the invention is an organic solvent, and the organic solvent is at least one of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dichloromethane, ethyl acetate, pyridine, 1, 4-dioxane, 1, 2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, ethanol, carbon tetrachloride, chloroform and N-butanol, preferably N-methylpyrrolidone.
(3) Alkali
The base in the present invention is an inorganic base, and the base is lithium carbonate, cesium carbonate, potassium carbonate, sodium acetate, lithium acetate, potassium phosphate, sodium tert-butoxide, lithium tert-butoxide or potassium tert-butoxide, and preferably sodium carbonate.
(4) Reaction temperature
In the preparation method of the present invention, the reaction temperature is 100 ℃ to 120 ℃, and can be, for example, but not limited to, 100 ℃, 110 ℃ and 120 ℃, and the reaction temperature is preferably 120 ℃.
(5) Reaction time
In the production method of the present invention, the reaction time is not particularly limited, and a suitable reaction time can be determined by detecting the remaining percentage of the target product or the raw material by liquid chromatography, and is usually 10 to 12 hours, such as 10 hours, 11 hours, or 12 hours, but is not limited thereto, and the reaction time is preferably 12 hours.
(6) Separating and purifying
The mixture obtained after the reaction can be further separated and purified to obtain a purer final product. Methods for separation and purification are well known to those skilled in the art, and for example, extraction, column chromatography, distillation, filtration, centrifugation, washing, fractionation, and adsorption, or a combination of at least two methods can be used for separation and purification, such as extraction and column chromatography.
Of course, if desired, the reaction mixture obtained can also be introduced directly into other processes for direct reaction to produce other products. Alternatively, the reaction mixture may be subjected to one or more of pretreatment, for example, concentration, extraction and distillation under reduced pressure, prior to introduction into other processes, to obtain a crude product or a pure product, which is then introduced into other processes.
In a preferred embodiment, the post-treatment step after the reaction is completed may be as follows: after the reaction is finished, cooling the reaction liquid, adding ethyl acetate for dilution, transferring the diluted solution into a separating funnel, extracting with saturated saline solution, separating out a water phase and an organic phase, extracting the water phase for 3 times with ethyl acetate, combining the organic phases, adding 5g of anhydrous sodium sulfate, standing for 30min, washing a filter cake for 3 times with 5mL of ethyl acetate each time, then spinning off the solvent, separating the concentrate through column chromatography (wherein the silica gel is 300-400-mesh silica gel), collecting eluent by taking the mixed liquid of petroleum ether and ethyl acetate as an eluent, and concentrating to obtain the target product.
The preparation method of the 1- (4-methylbenzyl) -3-morphininyl-4-methylselenylmaleimide provided by the invention has the following beneficial effects:
a) the reaction has high efficiency, high yield and simple and convenient post-treatment;
b) dimethyl diselenide is used as a methylselenylation reagent to participate in the series reaction of the three components;
c) cheap and easily available copper salt and oxygen are used as a catalytic system;
the invention takes dimethyl diselenide with a structure shown as a formula (I), N- (4-methylbenzyl) maleimide with a structure shown as a formula (II) and N-methylmaleimide with a structure shown as a formula (III) as reaction raw materials, and obtains the 1- (4-methylbenzyl) -3-morphininyl-4-methylselenobenzimide compound with a structure shown as a formula (IV) through the oxidative coupling reaction of carbon-carbon double bonds in the N-methylmaleimide structure under the catalysis of transition metal copper/oxygen. The synthesis method is an important development and supplement of the synthesis method of the 3-amino-4-alkylseleno maleimide, which is simple and convenient to operate and low in cost, provides a new strategy for molecular design and synthesis of maleimide derivatives, and has important social and economic meanings.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are only to illustrate the present invention, and the present invention is not limited to the actual scope of the present invention in any form, and the present invention is not limited to the scope of the present invention.
The data and purity of the novel compounds given in the following examples were determined by nuclear magnetic resonance.
Example 1
Synthesis of 1- (4-methylbenzyl) -3-morphininyl-4-methylseleno maleimide compound
N- (4-methylbenzyl) maleimide (0.2mmol, 1equiv), morpholine (0.3mmol, 1.5equiv), sodium carbonate (0.8mmol, 4equiv), copper acetate (0.02mmol, 0.1equiv) and 1mL of N-methylpyrrolidone were added to the reaction tube at room temperature, then charged with oxygen and replaced three times, and dimethyldiselenide (0.4mmo, 2equiv) was injected with a syringe and stirred at the reaction temperature of 120 ℃ for 12 hours. The reaction mixture was cooled, then ethyl acetate was added to dilute the reaction mixture, the diluted solution was transferred to a separatory funnel, extraction was performed with saturated brine, an aqueous phase and an organic phase were separated, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, 5g of anhydrous sodium sulfate was added, the mixture was left to stand for 30min, a filter cake was washed 3 times with 5mL of ethyl acetate each time, then the solvent was spun off, and the product was isolated by column chromatography to give a yellow liquid (eluent: petroleum ether: ether ═ 8: 1), with a yield of 80%, and a product weight of 61 mg.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz，CDCl3)：δ7.26(d，J＝7.8Hz，2H)，7.11(d，J＝7.8Hz，2H)，4.60(s，2H)，4.11(t，J＝ 4.70Hz，4H)，3.77(t，Ｊ＝4.70Hz，4H)，2.31(s，3H)，2.18(s，3H)；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz，CDCl3)：δ169.9，166.4，148.7，137.4，133.7，129.2，128.7，89.7，67.0，48.5，41.6，21.1， 9.6；
HRMS(ESI)：calcd for C17H20N2O3Se[M+H]+381.0718，found 381.0722。
as can be seen from the above example 1, when the method of the present invention is employed, 1- (4-methylbenzyl) -3-morphinanyl-4-methylselenylmaleimide compound can be obtained in high yield and high purity.
Examples 2 to 4
Examples 2 to 4 were each carried out in the same manner as in example 1 except that the transition metal catalyst copper acetate was replaced with the following copper salt, respectively, and the copper salt compounds used and the yields of the corresponding products were as shown in Table 1 below.
TABLE 1
As can be seen from Table 1 above, when other copper salts were used, cuprous iodide was able to react smoothly but the yield of the product decreased significantly, while cupric chloride and cupric bromide were not able to catalyze the reaction thereby demonstrating that cupric acetate is a key factor in the success of the reaction and is most effective for the reaction system.
Examples 5 to 19
Examples 5 to 19 were carried out in the same manner as in example 1 except that the organic solvent N-methylpyrrolidone was replaced with the following organic solvents, respectively, and the organic solvents used and the yields of the corresponding products were as shown in table 2 below.
TABLE 2
| Numbering | Solvent(s) | Reaction yield (%) |
| Example 5 | Dimethyl sulfoxide | 19 |
| Example 6 | N, N-dimethylformamide | 10 |
| Example 7 | N, N-dimethyl acetamide | 11 |
| Example 8 | Methylene dichloride | Is not reacted |
| Example 9 | Ethyl acetate | Is not reacted |
| Example 10 | Pyridine compound | Is not reacted |
| Example 11 | 1, 4-dioxahexaalkane | Is not reacted |
| Example 12 | 1, 2-dichloroethane | Is not reacted |
| Example 13 | Acetonitrile | Is not reacted |
| Example 14 | Toluene | Is not reacted |
| Example 15 | Tetrahydrofuran (THF) | Is not reacted |
| Example 16 | Ethanol | Is not reacted |
| Example 17 | Carbon tetrachloride | Is not reacted |
| Example 18 | Chloroform | Is not reacted |
| Example 19 | N-butanol | Is not reacted |
As can be seen from Table 2 above, when other organic solvents are used, the reaction can occur except in strongly polar solvents such as dimethyl sulfoxide and N, N-dimethylacetamide, but the yield is still reduced; without any product under non-polar or even weakly coordinating solvent conditions. This demonstrates that the proper selection of the organic solvent has a significant, even decisive influence on whether the reaction can proceed.
Examples 20 to 28
Examples 20 to 28 were each carried out in the same manner as in example 1 except that the alkali sodium carbonate therein was replaced with the following inorganic base, respectively, and the yields of the base compound used and the corresponding products are shown in the following table 3.
TABLE 3
| Numbering | Alkali | Reaction yield (%) |
| Example 20 | Cesium carbonate | Is not reacted |
| Example 21 | Lithium carbonate | Is not reacted |
| Example 22 | Potassium carbonate | Is not reacted |
| Example 23 | Potassium phosphate | Is not reacted |
| Example 24 | Sodium acetate | Is not reacted |
| Example 25 | Lithium acetate | Is not reacted |
| Example 26 | Lithium tert-butoxide | Is not reversedShould be taken |
| Example 27 | Sodium tert-butoxide | Is not reacted |
| Example 28 | Potassium tert-butoxide | Is not reacted |
As can be seen from Table 3 above, almost none of the bases reacted when other bases were used, thus demonstrating that sodium carbonate is a key factor in the success of the reaction and is most effective for the reaction system.
From the above, it is clear from all the examples that when the method of the present invention is adopted with a complex reaction system consisting of a transition metal catalyst (especially copper acetate), an inorganic base (especially sodium carbonate) and a suitable organic solvent (especially N-methylpyrrolidone), the 1- (4-methylbenzyl) -3-morphininyl-4-methylselenobeimide compound can be synthesized in high yield and high purity by three-component series reaction under oxygen condition, and a completely new synthetic route is provided for the efficient and rapid synthesis of the compound.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments are modified or some or all of the technical features are equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (3)
1. A preparation method of 1- (4-methylbenzyl) -3-amino-4-methylseleno maleimide compound is characterized in that dimethyl diselenide, N- (4-methylbenzyl) maleimide and morpholine are used as reaction raw materials in an organic solvent under the condition of oxygen, and under the catalysis of transition metal copper and alkali, 1- (4-methylbenzyl) -3-morphinyl-4-methylseleno maleimide compound is obtained through oxidative coupling reaction of carbon-carbon double bonds in an N- (4-methylbenzyl) maleimide structure;
the dimethyl diselenide is: MeSeMe
The N- (4-methylbenzyl) maleimide is:
the morpholine is as follows:
the 1- (4-methylbenzyl) -3-morphininyl-4-methylselenylmaleimide is prepared from the following components in percentage by weight:
the catalyst copper is copper acetate;
the alkali is sodium carbonate;
the organic solvent is N-methyl pyrrolidone.
2. The method as claimed in claim 1, wherein the reaction temperature is 100-120 ℃.
3. The process according to claim 1, wherein the reaction time is 10 to 12 hours.
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| CN111333564B (en) * | 2019-12-30 | 2023-08-18 | 温州医科大学 | Synthesis method of 3-alkylthio-1-methyl-4-morpholinylmaleimide compound |
| CN111393350B (en) * | 2019-12-30 | 2024-01-05 | 温州医科大学 | Synthesis method of N-methyl-3-substituted benzyl mercapto-4-morpholinyl maleimide compound |
| CN111620840B (en) * | 2020-06-17 | 2023-06-30 | 温州医科大学 | Synthesis method of 2-morpholino-3-arylseleno naphthoquinone |
| CN111606843A (en) * | 2020-06-17 | 2020-09-01 | 温州医科大学 | Synthetic method of 2-phenylseleno-3-amino-1, 4-naphthoquinone |
| CN111978235B (en) * | 2020-08-12 | 2023-08-18 | 温州医科大学 | Preparation method of 3-amino-4-methylmercapto maleimide compound |
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