CN111423354B - Synthesis method of 1H-3-pyrrolidone compound - Google Patents
Synthesis method of 1H-3-pyrrolidone compound Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
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- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
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Abstract
The invention provides a synthesis method of 1H-3-pyrrolidone compounds, which comprises the steps of taking aliphatic primary amine and beta-diketone compounds as raw materials, uniformly mixing the raw materials with an iron complex catalyst and a copper salt cocatalyst in an organic solvent, reacting for 8-12 hours at 40-110 ℃, and separating and purifying after the reaction is finished to obtain the 1H-3-pyrrolidone compounds. The purity of the product synthesized by the method can reach more than 99 percent (determined by HPLC) after purification, and the yield can reach 85 percent. The production process is simple, the production process is mild, and the emission is low, so that the process design can be directly carried out on the basis of laboratory work, and the large-scale production is realized.
Description
Technical Field
The invention relates to the technical field of organic chemical industry, in particular to a preparation method of fine chemicals 1H-3-pyrrolidone compounds, and specifically relates to a synthesis method of important organic chemical intermediates 1H-3-pyrrolidone compounds.
Background
The heterocyclic segment of the 1H-3-pyrrolidone compound is a structure which is common in natural products, medicaments and bioactive components, but the method for artificially synthesizing the structure is not a plurality of methods at present. Most of the existing methods have harsh conditions, or the reaction process is difficult to control due to factors such as heat release and the like, so that the industrial amplification is hindered. Therefore, it is practical to develop a fast, mild, green and efficient method for constructing the structural unit. According to literature, the compounds are synthesized by taking gamma-butyrolactone or maleic anhydride as a raw material and performing hydroamination, but the pyrrolidone synthesized by the methods is single in structure, and the cost is greatly increased if the pyrrolidone is further modified. According to early literature reports, the synthesis method of the 1H-3-pyrrolidone compound can be synthesized by acylation cyclization under the promotion of copper trifluoroacetate in trifluoroacetic acid solvent by using enamine ketone as a raw material, the reaction yield is about 85%, but the cost of a catalytic system is high, the industrialization is difficult to realize, the method for synthesizing the 1H-3-pyrrolidone compound is simple, the target product can be obtained by using acetylacetone and primary amine as raw materials under the catalysis of hydrogen peroxide, but the reaction rate is too high, the heat release is serious, the amplification is difficult to control, and the oxidation system generates more byproducts, so that the method is not suitable for large-scale industrial production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a new synthetic method for preparing 1H-3-pyrrolidone compounds. The technical problem to be solved is to select a new catalytic system to control the production cost, improve the yield and be suitable for industrial scale-up production.
The invention takes a beta-diketone compound and aliphatic primary amine as raw materials, and the target product is obtained by condensation and ring closure in an organic solvent under the condition of the existence of a catalyst. The chemical reaction formula is as follows:
the technical scheme of the invention is as follows:
a synthetic method of 1H-3-pyrrolidone compounds is characterized in that aliphatic primary amine and beta-diketone compounds shown in a formula (I) are used as raw materials, and a compound shown in a formula (II) (a target product: 1H-3-pyrrolidone compounds) is obtained after synthesis reaction, separation and purification, wherein the synthesis reaction is that the aliphatic primary amine, the beta-diketone compounds, an organic solvent, an iron complex catalyst and a copper salt cocatalyst are uniformly mixed and react for 8-12 hours at the temperature of 40-110 ℃; after the reaction is finished, separating and purifying to obtain a 1H-3-pyrrolidone compound;
in the formula (I) or formula (II), R1Is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, benzyl, p-chlorobenzyl, p-methylbenzyl, octyl or p-methoxybenzyl; r2Is methyl, ethyl, propyl, isopropyl or phenyl.
Preferably, the amount of the material of the catalyst (the sum of the amounts of the materials of the iron complex catalyst and the copper salt co-catalyst) is 1-5% of the amount of the aliphatic primary amine material on a molar basis; the mass ratio of the copper salt cocatalyst to the iron complex catalyst is 0.3:1-0.5: 1; still further, the amount of material of the catalyst is 3% of the amount of the aliphatic primary amine material on a molar basis; the mass ratio of the copper salt of the cocatalyst to the iron complex of the catalyst was 1:2.
Preferably, the ratio of the amount of the substance of the aliphatic primary amine to the amount of the substance of the beta-diketone compound is 1:2.0 to 2.4.
The iron complex catalyst is a complex formed by the reaction of an iron source and a ligand, preferably the iron source is ferric acetate, ferric chloride or ferric nitrate, and the ligand is 1, 10-phenanthroline, triphenylphosphine, L-proline, L-alanine or L-lysine; further, the iron complex catalyst is a complex formed by reacting iron chloride with 1, 10-phenanthroline.
Preferably, the copper salt promoter is selected from one or more of cuprous iodide, cuprous chloride, cupric oxide, cupric nitrate, cupric hydroxide and cupric acetate; further, the copper salt co-catalyst is cuprous iodide.
Preferably, the organic solvent is selected from one of toluene, xylene, DMSO, DMF, tetrahydrofuran, and 1, 4-dioxane; further, the organic solvent is toluene.
Preferably, the synthesis reaction temperature is 90 ℃ (90 ℃ ± 2 ℃, 2 ℃ is an error).
The specific operation steps are as follows:
(1) adding a beta-diketone compound and aliphatic primary amine into an organic solvent, adding a proportional amount of an iron complex catalyst and a copper salt cocatalyst while stirring, and reacting for 8-12 hours at 40-110 ℃;
(2) after the reaction is finished, adding distilled water into the reaction solution, stirring uniformly, separating two phases, extracting the water phase for three times by using ethyl acetate, combining organic phases, and drying by using anhydrous sodium sulfate;
(3) filtering the extractive solution, distilling under reduced pressure to remove solvent, separating the residual viscous substance by column chromatography or adding appropriate solvent for recrystallization to obtain pure product 1H-3-pyrrolidone.
The method has the advantages that the purity of the product synthesized by the method is more than or equal to 99 percent (determined by HPLC) after purification, and the yield reaches 85 percent; the catalyst is easy to obtain and low in cost, the production process is simple, the production process is mild, and the emission is low, so that the process design can be directly carried out on the basis of laboratory work, and the large-scale production can be realized.
Drawings
FIG. 1 is a single crystal diffractogram of the synthetic product of example 1.
Detailed Description
Example 1
A250 ml round bottom flask was charged with acetylacetone (22.0g, 220mmol), benzylamine (10.7g, 100mmol), complex of ferric chloride with 1, 10-phenanthroline (3.0mmol), cuprous iodide (1.5mmol), and toluene (100 ml). The stirring was turned on and the temperature was increased, and the reaction was carried out at 105 ℃ C. + -2 ℃ C. for 8 hours while keeping the bottle mouth open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. Filtering, distilling under reduced pressure, separating the concentrate with chromatographic column (the filler of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 by elution) or recrystallizing (the mixed solvent of acetone and ethyl acetate) to obtain colorless crystals 21.1g, the yield is 85%, the product purity is not less than 99% (determined by HPLC), the product is N-benzyl-1H-2-hydroxy-2-methyl-4-acetyl-5-methyl-3-pyrrolidone, and the single crystal diffraction result is shown in figure 1.
Example 2
A250 ml round-bottom flask was charged with acetylacetone (22.0g, 220mmol), n-butylamine (7.4g, 100mmol), a complex of iron nitrate with L-lysine (3.0mmol), cuprous iodide (1.5mmol) and toluene (100 ml). The stirring was turned on and the temperature was increased, and the reaction was carried out at 105 ℃ C. + -2 ℃ C. for 8 hours while keeping the bottle mouth open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation, and chromatographic column separation (the filler of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 by elution) or recrystallization separation (the mixed solvent of acetone and ethyl acetate) of the concentrate to obtain 15.1g of colorless crystals, the yield is 67%, the product purity is not less than 99% (determined by HPLC), and the product is N-butyl-1H-2-hydroxy-2-methyl-4-acetyl-5-methyl-3-pyrrolidone.
Example 3
A250 ml round-bottomed flask was charged with acetylacetone (22.0g, 220mmol), n-butylamine (7.4g, 100mmol), a complex of iron chloride with L-proline (3.0mmol), copper oxide (1.5mmol) and DMSO (100 ml). The stirring was turned on and the temperature was raised, and the reaction was carried out at 105 deg.C (105 deg.C. + -. 2 deg.C) for 8 hours while keeping the bottle mouth open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation, and chromatographic column separation (the filler of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 by elution) or recrystallization separation (the mixed solvent of acetone and ethyl acetate) of the concentrate to obtain 15.1g of colorless crystals, the yield is 67%, the product purity is not less than 99% (determined by HPLC), and the product is N-butyl-1H-2-hydroxy-2-methyl-4-acetyl-5-methyl-3-pyrrolidone.
Example 4
A250 mL round bottom flask was charged with benzoylacetone (35.6g, 220mmol), n-propylamine (5.9g, 100mmol), the complex of ferric chloride with 1, 10-phenanthroline (3.0mmol), cuprous iodide (1.5mmol) and toluene (100 mL). The stirring was turned on and the temperature was increased, and the reaction was carried out at 105 ℃ C. + -2 ℃ C. for 8 hours while keeping the bottle mouth open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation, and chromatographic column separation (the filler of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 by elution) or recrystallization separation (the mixed solvent of acetone and ethyl acetate) of the concentrate to obtain 19.2g of colorless crystals, the yield is 71%, the product purity is not less than 99% (determined by HPLC), and the product is N-propyl-1H-2-hydroxy-2-methyl-4-benzoyl-5-methyl-3-pyrrolidone.
Example 5
A250 ml round bottom flask was charged with acetylacetone (22.0g, 220mmol), p-chlorobenzylamine (14.1g, 100mmol), a complex of iron sulfate with 1, 10-phenanthroline (3.0mmol), cuprous iodide (1.5mmol) and xylene (100 ml). The stirring was turned on and the temperature was increased, and the reaction was carried out at 105 ℃ C. + -2 ℃ C. for 8 hours while keeping the bottle mouth open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation, and chromatographic column separation (the filling agent of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 by elution) or recrystallization separation (the mixed solvent of acetone and ethyl acetate) of the concentrate to obtain 23.1g of colorless crystals, wherein the yield is 79 percent, the product purity is more than or equal to 99 percent (determined by HPLC), and the product is N-p-chlorobenzyl-1H-2-hydroxy-2-methyl-4-acetyl-5-methyl-3-pyrrolidone.
Example 6
A250-mL round-bottom flask was charged with acetylacetone (22.0g, 220mmol), octylamine (7.3g, 100mmol), a complex of iron nitrate with 1, 10-phenanthroline (4.0mmol), cuprous iodide (2.0mmol), and toluene (100 mL). The stirring was turned on and the temperature was increased, and the reaction was carried out at 110 ℃ C. + -2 ℃ C. for 8 hours while keeping the neck open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation is carried out, and the concentrate is subjected to chromatographic column separation (the filler of the chromatographic column is silica gel, the eluting ratio of petroleum ether to ethyl acetate is 5:1) or recrystallization separation (the mixed solvent of acetone and ethyl acetate) to obtain 19.0g of colorless crystals, wherein the yield is 83 percent, the product purity is more than or equal to 99 percent (determined by HPLC), and the product is N-octyl-1H-2-hydroxy-2 methyl-4-acetyl-5 methyl-3-pyrrolidone.
Example 7
A250-mL round-bottom flask was charged with acetylacetone (22.0g, 220mmol), octylamine (7.3g, 100mmol), a complex of iron nitrate with 1, 10-phenanthroline (4.0mmol), cuprous iodide (2.0mmol), and toluene (100 mL). The stirring was turned on and the temperature was increased, and the reaction was carried out at 40 deg.C (40 deg.C. + -. 2 deg.C) for 8 hours while keeping the bottle mouth open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation, and chromatographic column separation (the filler of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 by elution) or recrystallization separation (the mixed solvent of acetone and ethyl acetate) of the concentrate to obtain 5.7g of colorless crystals, the yield is 25%, the product purity is not less than 99% (determined by HPLC), and the product is N-octyl-1H-2-hydroxy-2 methyl-4-acetyl-5 methyl-3-pyrrolidone.
Example 8
A250 mL round bottom flask was charged with acetylacetone (22.0g, 220mmol), octylamine (7.3g, 100mmol), a complex of ferric nitrate with 1, 10-phenanthroline (5.0mmol), cuprous iodide (3.0mmol), and toluene (100 mL). The stirring was turned on and the temperature was increased, and the reaction was carried out at 40 deg.C (40 deg.C. + -. 2 deg.C) for 12 hours while keeping the bottle mouth open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation, and chromatographic column separation (the filler of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 by elution) or recrystallization separation (the mixed solvent of acetone and ethyl acetate) of the concentrate to obtain 7.9g of colorless crystals, the yield is 35%, the product purity is not less than 99% (determined by HPLC), and the product is N-octyl-1H-2-hydroxy-2 methyl-4-acetyl-5 methyl-3-pyrrolidone.
Example 9
A250 mL round bottom flask was charged with acetylacetone (22.0g, 220mmol), octylamine (7.3g, 100mmol), a complex of ferric nitrate with 1, 10-phenanthroline (4.0mmol), cuprous iodide (1.2mmol), and toluene (100 mL). The stirring was turned on and the temperature was increased, and the reaction was carried out at 110 ℃ C. + -2 ℃ C. for 8 hours while keeping the neck open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation, and chromatographic column separation (the filler of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 by elution) or recrystallization separation (the mixed solvent of acetone and ethyl acetate) of the concentrate to obtain 14.5.0g of colorless crystals, wherein the yield is 63.4%, the product purity is not less than 99% (determined by HPLC), and the product is N-octyl-1H-2-hydroxy-2 methyl-4-acetyl-5 methyl-3-pyrrolidone.
Example 10
A250 mL round bottom flask was charged with acetylacetone (22.0g, 220mmol), octylamine (7.3g, 100mmol), a complex of ferric nitrate with 1, 10-phenanthroline (1.0mmol), cuprous iodide (0.5mmol), and toluene (100 mL). The stirring was turned on and the temperature was increased, and the reaction was carried out at 110 ℃ C. + -2 ℃ C. for 8 hours while keeping the neck open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation, and chromatographic column separation (the filler of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 by elution) or recrystallization separation (the mixed solvent of acetone and ethyl acetate) of the concentrate to obtain 9.5.0g of colorless crystals, the yield is 41.5%, the product purity is not less than 99% (determined by HPLC), and the product is N-octyl-1H-2-hydroxy-2 methyl-4-acetyl-5 methyl-3-pyrrolidone.
Example 11
A250 mL round bottom flask was charged with acetylacetone (22.0g, 220mmol), octylamine (7.3g, 100mmol), a complex of ferric nitrate with 1, 10-phenanthroline (4.0mmol), cuprous iodide (2.0mmol), and toluene (100 mL). The stirring was turned on and the temperature was increased, and the reaction was carried out at 90 deg.C (90 deg.C. + -. 2 deg.C) for 8 hours while keeping the bottle mouth open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation, and chromatographic column separation (the filler of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 by elution) or recrystallization separation (the mixed solvent of acetone and ethyl acetate) of the concentrate to obtain 19.0g of colorless crystals, the yield is 83%, the product purity is not less than 99% (determined by HPLC), and the product is N-octyl-1H-2-hydroxy-2 methyl-4-acetyl-5 methyl-3-pyrrolidone.
Comparative example 1
A250 ml round bottom flask was charged with acetylacetone (22.0g, 220mmol), benzylamine (10.7g, 100mmol), stirred open and warmed up, 24.9g of 30% hydrogen peroxide was added dropwise at 40 ℃ to react for 12 hours, while keeping the flask open. The temperature rise was stopped, 100ml of deionized water was then added, the two phases were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, reduced pressure distillation is carried out, the concentrate is subjected to chromatographic column separation (the filler of the chromatographic column is silica gel, the ratio of petroleum ether to ethyl acetate is 5:1 in terms of elution) or recrystallization separation (the mixed solvent of acetone and ethyl acetate), 16.1g of colorless crystals are obtained, the yield is 65%, the product purity is more than or equal to 90% (determined by HPLC), and the product N-benzyl-1H-2-hydroxy-2-methyl-4-acetyl-5-methyl-3-pyrrolidone contains more byproducts.
Claims (6)
1. A synthetic method of 1H-3-pyrrolidone compounds is characterized in that aliphatic primary amine and beta-diketone compounds shown in a formula (I) are used as raw materials, and the compounds shown in a formula (II) are obtained after synthesis reaction, separation and purification, and the method is characterized in that: the synthesis reaction is to uniformly mix aliphatic primary amine, a beta-diketone compound, an organic solvent, an iron complex catalyst and a copper cocatalyst and react for 8 to 12 hours at the temperature of between 40 and 110 ℃;
in the formula (I) or formula (II), R1Is methyl, ethyl, propyl, butyl, isopropyl, benzyl, p-chlorobenzyl, p-methylbenzyl, octyl or p-methoxybenzyl; r is2Is methyl, ethyl, propyl, isopropyl or phenyl;
the iron complex catalyst is a complex formed by the reaction of an iron source and a ligand, wherein the iron source is ferric acetate, ferric chloride or ferric nitrate, and the ligand is 1, 10-phenanthroline, triphenylphosphine, L-proline, L-alanine or L-lysine; the copper cocatalyst is one or more of cuprous iodide, cuprous chloride, cupric oxide, cupric nitrate, cupric hydroxide and cupric acetate.
2. The method for synthesizing 1H-3-pyrrolidone compounds as claimed in claim 1, wherein: the amount of the catalyst material accounts for 1-5% of the amount of the aliphatic primary amine material; the ratio of the amount of copper promoter to the amount of iron complex catalyst material is 0.3:1 to 0.5: 1.
3. The method for synthesizing 1H-3-pyrrolidones compounds according to claim 2, wherein: the amount of the substance of the catalyst is 3% of the amount of the aliphatic primary amine substance; the mass ratio of promoter copper to catalyst iron complex was 1:2.
4. A method of synthesis of 1H-3-pyrrolidones as claimed in any one of claims 1 to 3, characterized in that: the material quantity ratio of the aliphatic primary amine to the beta-diketone compound is 1: 2.0-2.4.
5. The method for synthesizing 1H-3-pyrrolidone compounds as claimed in claim 1, wherein: the organic solvent is toluene, xylene, DMSO, DMF, tetrahydrofuran or 1, 4-dioxane.
6. The method for synthesizing 1H-3-pyrrolidone compounds as claimed in claim 1, wherein: the synthesis reaction temperature is 90 ℃.
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