CN111018705A - Preparation method of tetrahydrocurcumin and intermediate thereof - Google Patents
Preparation method of tetrahydrocurcumin and intermediate thereof Download PDFInfo
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Abstract
The invention provides a preparation method of tetrahydrocurcumin and an intermediate thereof, wherein the preparation method of the intermediate comprises the steps of a, reacting a compound (IV) with an acetylation reagent in a solvent in the presence of alkali to obtain a compound (III); and b, in the presence of a catalyst and a solvent, carrying out reduction reaction on the compound (III) and hydrogen or a hydrogen donor to obtain a compound (II), namely a tetrahydrocurcumin intermediate, wherein the preparation method of the tetrahydrocurcumin comprises the step of removing acetyl from the compound (II) in the solvent in the presence of alkali to obtain a compound (I), namely the tetrahydrocurcumin. The diacetyl curcumin reduction reaction selectivity of the invention is far better than that of direct reduction curcumin, and the yield is high; the invention has simple and convenient purification and high product content, and almost does not contain curcumin, hexahydrocurcumin and octahydrocurcumin; the method has the advantages of simple and easy operation, stable and durable process, easy control, easy amplification, convenient treatment after reaction, and economic and convenient industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of tetrahydrocurcumin and an intermediate thereof.
Background
Curcumin is a natural polyphenol substance in turmeric plants, and has various pharmacological functions of resisting inflammation, resisting oxidation, protecting liver, removing oxygen free radicals, resisting tumor activity, preventing Alzheimer's disease and the like. Curcumin is rapidly metabolized in vivo to glucuronic acid conjugate, sulfuric acid conjugate, dihydrocurcumin, tetrahydrocurcumin and hexahydrocurcumin, which are converted to tetrahydrocurcumin (fig. 1). Curcumin has a very limited application due to its poor water solubility, poor photostability and low bioavailability. Tetrahydrocurcumin is the most main metabolite produced in the in-vivo metabolic process of curcumin, and is reported to be superior to curcumin in the aspects of antioxidation, blood sugar reduction, blood fat reduction, cancer resistance, depression resistance and the like, and the chemical formula of the tetrahydrocurcumin is as follows:
the literature reports that tetrahydrocurcumin is mostly obtained by catalytic hydrogenation of curcumin. In 2014, jaanxi jiahe disclosed a method for preparing tetrahydrocurcumin by catalytic hydrogenation of platinum-iron-nickel hydroxide composite nanoparticles in patent CN 104496779. However, the composition and preparation method of the platinum-iron-nickel hydroxide composite nanoparticles are not specifically described in the patent, and the method is not practical. The yield of the reaction is reported in the patent, but the purity of the product is not specified. Other documents mostly adopt Pd-C or PtO2Catalytic hydrogenation, wherein the main impurities are over-reduction products of hexahydrocurcumin and octahydrocurcumin, column chromatography is mostly adopted for purification, and the reaction yield is 40-80%. When the laboratory repeats the literature conditions, the selectivity is poor and the purification is difficult. Moreover, as the reaction scale is enlarged, the reaction time is prolonged, the over-reduced byproducts are obviously increased, and the reaction route of catalytic hydrogenation reduction of curcumin is as follows:
in 2011, Maehara et al in chem.pharm.Bull.,2011,59,1042-1044 reported that endophytic fungi in turmeric rhizome can carry out microbial transformation on curcumin to obtain a mixture of tetrahydrocurcumin, hexahydrocurcumin and octahydrocurcumin. However, this fungus and the biotransformation in which it participates do not have commercial prospects. 2017,15,30-34 of Zhejiang industry university report a method for preparing tetrahydrocurcumin by pichia pastoris biotransformation in a bioprocessing process, the mass concentration of the optimized substrate is only 50mg/L, and the yield is 77% after 24h of conversion. Although the efficiency of conversion is greatly improved compared with other reports, the purity of the product is low, 8.2 percent of curcumin remains, and in addition, a small amount of hexahydrocurcumin and unknown impurities exist.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of tetrahydrocurcumin and an intermediate thereof, and the tetrahydrocurcumin prepared by the method has the advantages of high purity, good selectivity, simple and convenient operation, low cost, suitability for industrial production and the like.
The technical scheme of the invention is as follows:
a preparation method of a tetrahydrocurcumin intermediate comprises the following steps:
a. reacting the compound IV with an acetylation reagent in a solvent in the presence of alkali to obtain a compound III;
b. in the presence of a catalyst and a solvent, the compound III and hydrogen or a hydrogen donor are subjected to reduction reaction to obtain a compound II, namely a tetrahydrocurcumin intermediate;
the reaction route is as follows:
in the preparation method of the tetrahydrocurcumin intermediate, the acetylation reagent in the step a is one or two of acetic anhydride or acetyl chloride; the base is one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane, preferably one or more of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane, preferably sodium carbonate, potassium carbonate, One or more of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane.
In the preparation method of the tetrahydrocurcumin intermediate, in the step a, the solvent is selected from benzene, toluene, chlorobenzene, xylene, isopropylbenzene, acetonitrile, benzonitrile, ethyl acetate, isopropyl acetate, 2-butanone, acetone, 1, 2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl ammonium phosphate, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, pyridine, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, tert-butanol, tert-amyl alcohol, polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-propylene glycol, diethoxymethane, dioxane, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran, and the like, One or more of N-hexane, cyclohexane, dichloromethane, 1, 2-dichloroethane, or chloroform, preferably one or more of toluene, dichloromethane, acetonitrile, ethylene glycol dimethyl ether, diethoxymethane, dioxane, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, tetrahydrofuran, or 2-methyltetrahydrofuran.
In the preparation method of the tetrahydrocurcumin intermediate, the feeding molar ratio of the acetylation reagent to the compound (IV) in the step a is 1.5-8: 1; preferably 1.8-4: 1; the feeding molar ratio of the alkali to the compound (IV) is 1.5-8:1, preferably 1.8-4: 1; the reaction temperature is-78-150 ℃, and preferably-10-130 ℃; the reaction time is 0.5 to 36 hours, preferably 1 to 24 hours.
In the preparation method of the tetrahydrocurcumin intermediate, the catalyst in the step b is one or more of raney nickel, palladium carbon, palladium black, palladium hydroxide/carbon, platinum carbon or platinum oxide, and raney nickel is preferred; the reducing agent is hydrogen or a hydrogen donor, and the hydrogen donor condition is one or more of ammonium formate, triethylamine/formic acid, cyclohexene or isopropanol, preferably hydrogen and ammonium formate; the solvent is selected from benzene, toluene, chlorobenzene, xylene, isopropylbenzene, acetonitrile, benzonitrile, ethyl acetate, isopropyl acetate, 2-butanone, acetone, 1, 2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl ammonium phosphate, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, pyridine, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, t-butanol, t-amyl alcohol, polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-propylene glycol, diethoxymethane, dioxane, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane, cyclohexane, dichloromethane, toluene, ethyl acetate, isopropyl alcohol, ethylene glycol, t-butyl alcohol, t-amyl alcohol, One or more of 1, 2-dichloroethane, or chloroform; preferably one or more of toluene, acetone, 2-butanone, isopropyl acetate, dichloromethane, acetonitrile, ethylene glycol dimethyl ether, diethoxymethane, dioxane, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, tetrahydrofuran, or 2-methyltetrahydrofuran.
In the preparation method of the tetrahydrocurcumin intermediate, when the catalyst is one or more of palladium carbon, palladium black, palladium hydroxide/carbon, platinum carbon or platinum oxide, the mass ratio of the palladium or palladium content in the catalyst to the feeding amount of the compound (II) is 0.001-0.5:1, preferably 0.005-0.2: 1; when the catalyst is Raney nickel, the mass ratio of the catalyst to the compound (II) is 0.001-0.5:1, preferably 0.005-0.2: 1.
In the preparation method of the tetrahydrocurcumin intermediate, when the reducing agent is hydrogen, the reaction is carried out at 1-10 atmospheric pressures, preferably 1-3 atmospheric pressures; when the hydrogen donor is ammonium formate, formic acid/triethylamine or cyclohexene, the molar ratio of the hydrogen donor to the compound (II) is 1.8-8:1, preferably 1.8-5: 1; when the hydrogen donor is methanol, ethanol or isopropanol, the mass ratio of the hydrogen donor to the compound (II) is 1-100:1, preferably 1-10: 1; the reaction temperature is-78-150 ℃, and preferably-10-130 ℃; the reaction time is 0.5 to 36 hours, preferably 1 to 24 hours.
A method for producing tetrahydrocurcumin from the tetrahydrocurcumin intermediate comprises the step of removing acetyl from a compound II in a solvent in the presence of alkali to obtain a compound I, namely tetrahydrocurcumin.
The reaction route is as follows:
in the method for preparing tetrahydrocurcumin, the base is one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, lithium hydroxide, sodium hydroxide, potassium hydroxide, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane, and preferably one or more of sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide; the solvent is selected from benzene, toluene, chlorobenzene, xylene, isopropylbenzene, acetonitrile, benzonitrile, ethyl acetate, isopropyl acetate, 2-butanone, acetone, 1, 2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl ammonium phosphate, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, pyridine, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, t-butanol, t-amyl alcohol, polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-propylene glycol, diethoxymethane, dioxane, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane, cyclohexane, dichloromethane, toluene, ethyl acetate, isopropyl alcohol, ethylene glycol, t-butyl alcohol, t-amyl alcohol, One or more of 1, 2-dichloroethane, chloroform, or water; preferably one or more of methanol, ethanol, tetrahydrofuran or water.
In the tetrahydrocurcumin preparation method, the equivalent ratio of the alkali to the compound (II) is 1.8-8:1, preferably 2-4: 1; the reaction temperature is selected from-10-150 ℃, and preferably 0-100 ℃; the reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.
Compared with the prior art, the invention has the following advantages: (1) the diacetyl curcumin reduction reaction selectivity of the invention is far better than that of direct reduction curcumin, and the yield is high; (2) the invention has simple and convenient purification and high product content, and almost does not contain curcumin, hexahydrocurcumin and octahydrocurcumin; (3) the method has the advantages of simple and easy operation, stable and durable process, easy control, easy amplification, convenient treatment after reaction, and economic and convenient industrial production.
Drawings
FIG. 1 is a liquid chromatogram of example 9 of the present invention.
Detailed Description
The invention is further illustrated by the following examples, which are intended to be purely exemplary of the invention. These examples are not meant to impose any limitation on the invention. It will be apparent that those skilled in the art can make various changes and modifications to the present invention within the scope and spirit of the present invention. It is to be understood that the invention is intended to cover such alternatives and modifications as may be included within the scope of the appended claims.
Example 1
The synthesis of diacetyl tetrahydrocurcumin as the intermediate of tetrahydrocurcumin adopts a synthetic route of
Toluene (500mL), curcumin (100g, 271mmol), triethylamine (68.3g, 675mmol), acetic anhydride (63.3g, 620mmol) and nitrogen were sequentially charged into a three-necked flask and replaced with nitrogen three times; heating to 50 deg.C, reacting for 5h, detecting by TLC, cooling to 0 deg.C, stirring for 0.5h, filtering, transferring the solid into three-necked bottle, adding 300mL water, stirring for 0.5h at 20 deg.C, filtering, and drying to obtain the final productTo yellow solid diacetylcurcumin (116g, 95%).1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝15.9Hz,2H),7.52(d,J＝1.9Hz,2H),7.33(dd,J＝8.2,1.9Hz,2H),7.16(d,J＝8.2Hz,2H),6.99(d,J＝15.9Hz,2H),6.21(s,1H),3.85(s,6H),2.28(s,6H).
Acetone (1.5L), diacetylcurcumin (150g, 331mmol), Raney nickel (15g) were put into a three-necked flask in this order and replaced with hydrogen three times. Reacting at 20 deg.C under hydrogen atmosphere (1atm) for 20h, detecting by HPLC that the raw materials are basically completely reacted, filtering, adding activated carbon into mother liquor, stirring for 1h, filtering, concentrating the mother liquor to dryness, adding methanol (750mL), stirring at 50 deg.C to clarify, slowly cooling to-5 deg.C, stirring for 1h, filtering, and drying to obtain pale yellow solid diacetyl tetrahydrocurcumin (135g, 90%).1H NMR(400MHz,DMSO-d6)δ7.04–6.92(m,4H),6.78(ddd,J＝10.2,7.9,1.9Hz,2H),3.75(s,6H),2.85(t,J＝7.4Hz,4H),2.78(d,J＝7.2Hz,2H),2.66(t,J＝7.8Hz,2H),2.23(s,6H)。
Example 2
The synthesis of diacetyl tetrahydrocurcumin as the intermediate of tetrahydrocurcumin adopts a synthetic route of
Dichloromethane (500mL), curcumin (100g, 271mmol), triethylamine (68.3g, 675mmol), acetic anhydride (63.3g, 620mmol) and nitrogen were put into a three-necked flask in this order and replaced with nitrogen three times; heating to 40 ℃, reacting for 4h, reducing the temperature to 10 ℃ after TLC detection reaction, stirring for 1h, filtering, transferring the solid into a three-necked bottle, adding 300mL of water, stirring for 2h at 30 ℃, filtering, and drying to obtain yellow solid diacetylcurcumin (116g, 95%).1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝15.9Hz,2H),7.52(d,J＝1.9Hz,2H),7.33(dd,J＝8.2,1.9Hz,2H),7.16(d,J＝8.2Hz,2H),6.99(d,J＝15.9Hz,2H),6.21(s,1H),3.85(s,6H),2.28(s,6H).
Acetone (1.5L), diacetylcurcumin (150g, 331mmol), Raney nickel (15g) were put into a three-necked flask in this order and replaced with hydrogen three times. Reacting at 30 deg.C for 15 hr under hydrogen atmosphere (3atm), detecting by HPLC that the raw materials are basically completely reacted, filtering, adding activated carbon into mother liquor, stirring for 0.5 hrFiltering, concentrating the mother liquor, adding methanol (750mL), stirring at 60 deg.C to clarify, slowly cooling to-5 deg.C, stirring for 1h, filtering, and drying to obtain pale yellow solid diacetyl tetrahydrocurcumin (138g, 91%).1H NMR(400MHz,DMSO-d6)δ7.04–6.92(m,4H),6.78(ddd,J＝10.2,7.9,1.9Hz,2H),3.75(s,6H),2.85(t,J＝7.4Hz,4H),2.78(d,J＝7.2Hz,2H),2.66(t,J＝7.8Hz,2H),2.23(s,6H)。
Example 3
The synthesis of diacetyl tetrahydrocurcumin as the intermediate of tetrahydrocurcumin adopts a synthetic route of
Into a three-necked flask were charged acetonitrile (1000mL), curcumin (200g, 542mmol), diisopropylethylamine (129.25g, 1000mmol), acetyl chloride (78.5g, 1000mmol) in this order, and nitrogen gas was substituted four times; heating to 80 deg.C, reacting for 3h, detecting by TLC, cooling to 0-10 deg.C, stirring for 2h, filtering, transferring the solid into a three-necked bottle, adding 400mL water, stirring at 30 deg.C for 3h, filtering, and drying to obtain yellow solid diacetylcurcumin (230g, 94%).1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝15.9Hz,2H),7.52(d,J＝1.9Hz,2H),7.33(dd,J＝8.2,1.9Hz,2H),7.16(d,J＝8.2Hz,2H),6.99(d,J＝15.9Hz,2H),6.21(s,1H),3.85(s,6H),2.28(s,6H).
Cumene (2L), diacetylcurcumin (150g, 331mmol), raney nickel (20g) were put into a three-necked flask in this order and replaced with hydrogen three times. Reacting at 20 ℃ for 20h under hydrogen atmosphere (2atm), detecting by HPLC that the raw materials are basically completely reacted, filtering, adding activated carbon into mother liquor, stirring for 2h, filtering, concentrating the mother liquor to dryness, adding ethanol (800mL), stirring at 80 ℃ to be clear, slowly cooling to-10 ℃, stirring for 2h, filtering, and drying to obtain light yellow solid diacetyl tetrahydrocurcumin (125g, 82%).1H NMR(400MHz,DMSO-d6)δ7.04–6.92(m,4H),6.78(ddd,J＝10.2,7.9,1.9Hz,2H),3.75(s,6H),2.85(t,J＝7.4Hz,4H),2.78(d,J＝7.2Hz,2H),2.66(t,J＝7.8Hz,2H),2.23(s,6H)。
Example 4
The synthesis of diacetyl tetrahydrocurcumin as the intermediate of tetrahydrocurcumin adopts a synthetic route of
NMP (1000mL), curcumin (200g, 542mmol), diisopropylethylamine (129.25g, 1000mmol), acetyl chloride (78.5g, 1000mmol), and nitrogen substitution were sequentially charged into a three-necked flask four times; heating to 150 deg.C, reacting for 0.5h, detecting by TLC, cooling to 10 deg.C, adding 4000mL water, stirring at 50 deg.C for 1h, filtering, and drying to obtain yellow solid diacetylcurcumin (221g, 90%).1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝15.9Hz,2H),7.52(d,J＝1.9Hz,2H),7.33(dd,J＝8.2,1.9Hz,2H),7.16(d,J＝8.2Hz,2H),6.99(d,J＝15.9Hz,2H),6.21(s,1H),3.85(s,6H),2.28(s,6H).
Cumene (2L), diacetylcurcumin (150g, 331mmol), raney nickel (20g) were put into a three-necked flask in this order and replaced with hydrogen three times. Reacting for 15h at 30 ℃ under hydrogen atmosphere (1atm), detecting the basic complete reaction of raw materials by HPLC, filtering, adding activated carbon into mother liquor, stirring for 1h, filtering, concentrating the mother liquor to dryness, adding ethanol (800mL), stirring at 80 ℃ to be clear, slowly cooling to 10 ℃, stirring for 1h, filtering, and drying to obtain light yellow solid diacetyl tetrahydrocurcumin (127g, 84%).1H NMR(400MHz,DMSO-d6)δ7.04–6.92(m,4H),6.78(ddd,J＝10.2,7.9,1.9Hz,2H),3.75(s,6H),2.85(t,J＝7.4Hz,4H),2.78(d,J＝7.2Hz,2H),2.66(t,J＝7.8Hz,2H),2.23(s,6H)。
Example 5
The synthesis of diacetyl tetrahydrocurcumin as the intermediate of tetrahydrocurcumin adopts a synthetic route of
Toluene (300ml), dichloromethane (300ml), acetonitrile (400ml), curcumin (133g, 361mmol), sodium bicarbonate (40g, 476mmol), sodium carbonate (40g, 482mmol), potassium bicarbonate (40g, 400mmol), acetyl chloride (19.62g, 250mmol), acetic anhydride (20.4g, 200mmol) were put into a three-necked flask in this order and replaced with nitrogen three times; reaction temperature-10 deg.C, reactionThe TLC detection reaction is finished for 24h, the temperature is reduced to 0 ℃, the stirring is carried out for 2h, the filtration is carried out, the solid is transferred to a three-necked bottle, 500mL of water is added, the stirring is carried out for 1.5h at the temperature of 30 ℃, the filtration and the drying are carried out, and yellow solid diacetylcurcumin (56g, 96%) is obtained.1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝15.9Hz,2H),7.52(d,J＝1.9Hz,2H),7.33(dd,J＝8.2,1.9Hz,2H),7.16(d,J＝8.2Hz,2H),6.99(d,J＝15.9Hz,2H),6.21(s,1H),3.85(s,6H),2.28(s,6H).
Adding toluene (0.5L), acetone (0.3L), 2-butanone (0.6L), ethylene glycol dimethyl ether (1L), diacetyl curcumin (300g, 662mmol), palladium carbon (5g), platinum carbon (5g), palladium hydroxide carbon (5g), ammonium formate (10g) and cyclohexene (10g) in sequence into a three-neck flask, reacting at-10 ℃ for 24 hours, detecting that the raw materials are basically completely reacted by HPLC, filtering, adding activated carbon into mother liquor, stirring for 3 hours, filtering, adding ethanol (800mL) after the mother liquor is concentrated to dryness, stirring to be clear at 80 ℃, slowly cooling to 0 ℃, stirring for 3 hours, filtering, and drying to obtain pale yellow solid diacetyl tetrahydrocurcumin (272g, 90%).1H NMR(400MHz,DMSO-d6)δ7.04–6.92(m,4H),6.78(ddd,J＝10.2,7.9,1.9Hz,2H),3.75(s,6H),2.85(t,J＝7.4Hz,4H),2.78(d,J＝7.2Hz,2H),2.66(t,J＝7.8Hz,2H),2.23(s,6H)。
Example 6
The synthesis of diacetyl tetrahydrocurcumin as the intermediate of tetrahydrocurcumin adopts a synthetic route of
Toluene (300ml), dichloromethane (300ml), acetonitrile (400ml), curcumin (133g, 361mmol), sodium bicarbonate (40g, 476mmol), sodium carbonate (40g, 482mmol), potassium bicarbonate (40g, 400mmol), acetyl chloride (19.62g, 250mmol), acetic anhydride (20.4g, 200mmol) were put into a three-necked flask in this order and replaced with nitrogen three times; the reaction temperature is 0 ℃, the reaction time is 20 hours, the TLC detection reaction is finished, the temperature is reduced to 10 ℃, the stirring time is 2 hours, the filtration is carried out, the solid is transferred to a three-necked bottle, 500mL of water is added, the stirring time is 1.5 hours at 40 ℃, the filtration and the drying are carried out, and yellow solid diacetylcurcumin (156g, 96%) is obtained. 1H NMR (400MHz, DMSO-d6) δ 7.66(d, J ═ 15.9Hz,2H),7.52(d, J ═ 1.9Hz,2H),7.33(dd, J ═ 8.2,1.9Hz,2H),7.16(d, J ═ 8.2Hz,2H),6.99(d, J ═ 15.9Hz,2H),6.21(s,1H),3.85(s,6H),2.28(s,6H).
Sequentially adding toluene (0.5L), 2-butanone (0.9L), ethylene glycol dimethyl ether (1L), diacetyl curcumin (300g, 662mmol), palladium carbon (5g), platinum carbon (5g), palladium hydroxide carbon (5g), ammonium formate (10g) and cyclohexene (10g) into a three-neck flask, reacting for 1h at the temperature of 100 ℃, detecting that the raw materials are basically completely reacted by HPLC, filtering, adding activated carbon into mother liquor, stirring for 3h, filtering, adding ethanol (800mL) after the mother liquor is concentrated to be dry, stirring to be clear at the temperature of 80 ℃, slowly cooling to 0 ℃, stirring for 2h, filtering, and drying to obtain light yellow solid diacetyl tetrahydrocurcumin (278g, 92%).1H NMR(400MHz,DMSO-d6)δ7.04–6.92(m,4H),6.78(ddd,J＝10.2,7.9,1.9Hz,2H),3.75(s,6H),2.85(t,J＝7.4Hz,4H),2.78(d,J＝7.2Hz,2H),2.66(t,J＝7.8Hz,2H),2.23(s,6H)。
Example 7
The synthesis of diacetyl tetrahydrocurcumin as the intermediate of tetrahydrocurcumin adopts a synthetic route of
Diethoxymethane (500mL), curcumin (66.24g, 180mmol), triethylamine (32.8g, 324mmol), acetic anhydride (33.1g, 324mmol) and nitrogen were put into a three-necked flask in this order and replaced three times; heating to 50 deg.C, reacting for 0.5h, detecting by TLC, cooling to 0 deg.C, stirring for 0.5h, filtering, transferring the solid into a three-necked bottle, adding 300mL water, stirring at 20 deg.C for 0.5h, filtering, and drying to obtain yellow solid diacetylcurcumin (74g, 91%).1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝15.9Hz,2H),7.52(d,J＝1.9Hz,2H),7.33(dd,J＝8.2,1.9Hz,2H),7.16(d,J＝8.2Hz,2H),6.99(d,J＝15.9Hz,2H),6.21(s,1H),3.85(s,6H),2.28(s,6H).
Acetone (1.5L), diacetylcurcumin (150g, 331mmol), Raney nickel (15g) were put into a three-necked flask in this order and replaced with hydrogen three times. Reacting under hydrogen atmosphere (1atm) at 20 deg.C for 20 hr, detecting by HPLC that the raw materials are basically completely reacted, filtering, adding activated carbon into mother liquor, stirring for 1 hr, filtering, concentrating the mother liquor, drying, and adding methanol (methanol)750mL), stirred to be clear at 50 ℃, slowly cooled to-5 ℃, stirred for 1h, filtered and dried to obtain light yellow solid diacetyl tetrahydrocurcumin (136g, 90%).1H NMR(400MHz,DMSO-d6)δ7.04–6.92(m,4H),6.78(ddd,J＝10.2,7.9,1.9Hz,2H),3.75(s,6H),2.85(t,J＝7.4Hz,4H),2.78(d,J＝7.2Hz,2H),2.66(t,J＝7.8Hz,2H),2.23(s,6H)。
Example 8
The synthesis of diacetyl tetrahydrocurcumin as the intermediate of tetrahydrocurcumin adopts a synthetic route of
Tetrahydrofuran (500mL), curcumin (147.2g, 400mmol), triethylamine (162g, 1600mmol), acetic anhydride (163.4g, 1600mmol) and nitrogen were put into a three-necked flask in sequence for three times; heating to 50 deg.C, reacting for 0.5h, detecting by TLC, cooling to 0 deg.C, stirring for 0.5h, filtering, transferring the solid into a three-necked bottle, adding 300mL water, stirring at 20 deg.C for 0.5h, filtering, and drying to obtain yellow solid diacetylcurcumin (164.5g, 91%).1H NMR(400MHz,DMSO-d6)δ7.66(d,J＝15.9Hz,2H),7.52(d,J＝1.9Hz,2H),7.33(dd,J＝8.2,1.9Hz,2H),7.16(d,J＝8.2Hz,2H),6.99(d,J＝15.9Hz,2H),6.21(s,1H),3.85(s,6H),2.28(s,6H).
Acetone (1.5L), diacetylcurcumin (150g, 331mmol), Raney nickel (15g) were put into a three-necked flask in this order and replaced with hydrogen three times. Reacting at 20 ℃ for 20h under hydrogen atmosphere (1atm), detecting by HPLC that the raw materials are basically completely reacted, filtering, adding activated carbon into mother liquor, stirring for 1h, filtering, concentrating the mother liquor to dryness, adding methanol (750mL), stirring at 50 ℃ to be clear, slowly cooling to-5 ℃, stirring for 1h, filtering, and drying to obtain light yellow solid diacetyl tetrahydrocurcumin (139g, 92%).1H NMR(400MHz,DMSO-d6)δ7.04–6.92(m,4H),6.78(ddd,J＝10.2,7.9,1.9Hz,2H),3.75(s,6H),2.85(t,J＝7.4Hz,4H),2.78(d,J＝7.2Hz,2H),2.66(t,J＝7.8Hz,2H),2.23(s,6H)。
Example 9
The synthesis route of tetrahydrocurcumin is as follows:
adding methanol (1.7L) and diacetyl tetrahydrocurcumin (330g, 723mmol) into a three-neck flask in sequence, controlling the temperature to be 10 ℃, dropwise adding a sodium hydroxide aqueous solution (50 percent and 130g), reacting at 10 ℃ for 5 hours, detecting that the reaction is almost complete by TLC, cooling to 5 ℃, adjusting the pH to 3 by using dilute hydrochloric acid, stirring at 0 ℃ for 2 hours, filtering, adding a solid into water (1L), stirring at 20 ℃ for 1 hour, filtering, adding a wet product into ethanol (2.5L), heating to 50 ℃, dissolving under stirring, adding activated carbon, continuously stirring for 1 hour, cooling to 20 ℃, filtering, concentrating a mother solution to 1L of ethanol, cooling to-10-0 ℃, stirring for 1 hour, filtering, and drying to obtain a white-like solid (242g, 90%).1H NMR(400MHz,DMSO-d6)δ8.68(br,2H),6.77(dd,J＝13.2,2.0Hz,2H),6.67(dd,J＝8.0,2.6Hz,2H),6.58(ddd,J＝11.2,8.0,2.0Hz,2H),3.74(s,6H),3.70(d,J＝4.3Hz,1H),2.80–2.70(m,4H),2.70–2.62(m,2H),2.57(dd,J＝8.7,6.8Hz,2H).
Liquid phase conditions:
example 10
The synthesis route of tetrahydrocurcumin is as follows:
adding methanol (1.7L) and diacetyl tetrahydrocurcumin (330g, 723mmol) into a three-neck flask in sequence, controlling the temperature to be 20 ℃, dropwise adding a sodium hydroxide aqueous solution (50 percent and 130g), reacting at 20 ℃ for 2 hours, detecting that the reaction is almost complete by TLC, cooling to 10 ℃, adjusting the pH to 4 by using dilute hydrochloric acid, stirring at 10 ℃ for 1 hour, filtering, adding the solid into water (1L), stirring at 30 ℃ for 0.5 hour, filtering, adding the wet product into ethanol (2.5L), heating to 60 ℃, dissolving under stirring, adding activated carbon, continuously stirring for 1 hour, cooling to 30 ℃, filtering, concentrating the mother liquor to 1.5L of ethanol, cooling to 0 ℃, stirring for 1 hour, filtering, and drying to obtain a white-like solid (235g, 87%).1H NMR(400MHz,DMSO-d6)δ8.68(br,2H),6.77(dd,J＝13.2,2.0Hz,2H),6.67(dd,J＝8.0,2.6Hz,2H),6.58(ddd,J＝11.2,8.0,2.0Hz,2H),3.74(s,6H),3.70(d,J＝4.3Hz,1H),2.80–2.70(m,4H),2.70–2.62(m,2H),2.57(dd,J＝8.7,6.8Hz,2H).
Example 11
The synthesis route of tetrahydrocurcumin is as follows:
adding methanol (1L), ethanol (0.5L), water (0.5L), diacetyl tetrahydrocurcumin (465g, 1000mmol) into a three-neck flask in sequence, dropwise adding a mixed aqueous solution (30%, 450g) of sodium hydroxide and sodium carbonate at a controlled temperature of 0 ℃, reacting for 24h at the temperature of 0 ℃, basically completely detecting by TLC, cooling to 5 ℃, adjusting the pH to 3 with dilute hydrochloric acid, stirring for 2h at the temperature of 0 ℃, filtering, adding a solid into water (2L), stirring for 1h at the temperature of 20 ℃, filtering, adding a wet product into ethanol (3.5L), heating to 50 ℃, dissolving under stirring, adding activated carbon, continuously stirring for 1h, cooling to 20 ℃, filtering, concentrating a mother solution to 1L, cooling to-10 ℃, stirring for 1h, filtering, and drying to obtain a white-like solid (345g, 91%).1H NMR(400MHz,DMSO-d6)δ8.68(br,2H),6.77(dd,J＝13.2,2.0Hz,2H),6.67(dd,J＝8.0,2.6Hz,2H),6.58(ddd,J＝11.2,8.0,2.0Hz,2H),3.74(s,6H),3.70(d,J＝4.3Hz,1H),2.80–2.70(m,4H),2.70–2.62(m,2H),2.57(dd,J＝8.7,6.8Hz,2H).
Example 12
The synthesis route of tetrahydrocurcumin is as follows:
sequentially adding methanol (1L), ethanol (0.5L), water (0.5L), and diacetyl tetrahydrocurcumin (465g, 1000mmol), dropwise adding mixed aqueous solution (30%, 800g) of sodium hydroxide and sodium carbonate at 100 deg.C, reacting at 100 deg.C for 1 hr, detecting by TLC to obtain a substantially complete reaction, cooling to 10 deg.C, adjusting pH to 4 with dilute hydrochloric acid, stirring at 10 deg.C for 1 hr, filtering, adding solid into water (1L), stirring at 30 deg.C for 0.5 hr, and filteringFiltering, adding the wet product into ethanol (2.5L), heating to 60 deg.C, stirring for dissolving, adding active carbon, stirring for 1 hr, cooling to 30 deg.C, filtering, concentrating the mother liquor to 1.5L, cooling to 0 deg.C, stirring for 1 hr, filtering, and drying to obtain white-like solid (360g, 95%).1H NMR(400MHz,DMSO-d6)δ8.68(br,2H),6.77(dd,J＝13.2,2.0Hz,2H),6.67(dd,J＝8.0,2.6Hz,2H),6.58(ddd,J＝11.2,8.0,2.0Hz,2H),3.74(s,6H),3.70(d,J＝4.3Hz,1H),2.80–2.70(m,4H),2.70–2.62(m,2H),2.57(dd,J＝8.7,6.8Hz,2H).
Comparative example
TABLE-direct reduction of curcumin
Note: the reaction in the table is 10g scale, and the conclusion is that the reaction solution is the result; the tetrahydro is tetrahydrocurcumin, the hexahydro is hexahydrocurcumin, and the octahydro is octahydrocurcumin.
Reduction of epidiacetylcurcumin
Note: the reaction in the table is 10g scale, and the conclusion is that the reaction solution is the result; the tetrahydro is diacetyl tetrahydrocurcumin, and the hexahydro is diacetyl hexahydrocurcumin.
The first table shows a comparative example of preparing tetrahydrocurcumin by directly reducing curcumin, and the second table shows an example of preparing diacetyl tetrahydrocurcumin by reducing diacetyl tetrahydrocurcumin according to the method provided by the invention.
The above is only a preferred embodiment of the present invention, and it should be noted that the above preferred embodiment should not be considered as limiting the present invention, and the protection scope of the present invention should be subject to the scope defined by the claims. It will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the spirit and scope of the invention, and these modifications and adaptations should be considered within the scope of the invention.
Claims (10)
1. A preparation method of a tetrahydrocurcumin intermediate is characterized by comprising the following steps:
a. reacting the compound (IV) with an acetylation reagent in a solvent in the presence of a base to obtain a compound (III);
b. in the presence of a catalyst and a solvent, reducing the compound (III) and hydrogen or a hydrogen donor to obtain a compound (II), namely a tetrahydrocurcumin intermediate; the reaction route is as follows:
2. the method for preparing a tetrahydrocurcumin intermediate as claimed in claim 1, wherein said acetylating agent in step a is one or both of acetic anhydride and acetyl chloride;
the base is one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane, preferably one or more of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane, preferably sodium carbonate, potassium carbonate, One or more of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane;
the solvent is selected from benzene, toluene, chlorobenzene, xylene, isopropylbenzene, acetonitrile, benzonitrile, ethyl acetate, isopropyl acetate, 2-butanone, acetone, 1, 2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl ammonium phosphate, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, pyridine, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, t-butanol, t-amyl alcohol, polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-propylene glycol, diethoxymethane, dioxane, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane, cyclohexane, dichloromethane, toluene, ethyl acetate, isopropyl alcohol, ethylene glycol, t-butyl alcohol, t-amyl alcohol, 1, 2-dichloroethane, or chloroform, preferably one or more of toluene, dichloromethane, acetonitrile, ethylene glycol dimethyl ether, diethoxymethane, dioxane, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, tetrahydrofuran, or 2-methyltetrahydrofuran.
3. The method for preparing a tetrahydrocurcumin intermediate as claimed in claim 1, wherein in the step a, the feeding molar ratio of the acetylation reagent to the compound (IV) is 1.5-8: 1; preferably 1.8-4: 1; the feeding molar ratio of the alkali to the compound (IV) is 1.5-8:1, preferably 1.8-4: 1; the reaction temperature is-78-150 ℃, and preferably-10-130 ℃; the reaction time is 0.5 to 36 hours, preferably 1 to 24 hours.
4. The method for preparing the tetrahydrocurcumin intermediate as claimed in claim 1, wherein in the step b, the catalyst is one or more of raney nickel, palladium carbon, palladium black, palladium hydroxide, palladium/carbon hydroxide, platinum carbon or platinum oxide, preferably raney nickel; the reducing agent is hydrogen or a hydrogen donor, and the hydrogen donor condition is one or more of ammonium formate, triethylamine/formic acid, cyclohexene or isopropanol, preferably hydrogen and ammonium formate; the solvent is selected from benzene, toluene, chlorobenzene, xylene, isopropylbenzene, acetonitrile, benzonitrile, ethyl acetate, isopropyl acetate, 2-butanone, acetone, 1, 2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl ammonium phosphate, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, pyridine, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, t-butanol, t-amyl alcohol, polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-propylene glycol, diethoxymethane, dioxane, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane, cyclohexane, dichloromethane, toluene, ethyl acetate, isopropyl alcohol, ethylene glycol, t-butyl alcohol, t-amyl alcohol, One or more of 1, 2-dichloroethane, or chloroform; preferably one or more of toluene, acetone, 2-butanone, isopropyl acetate, dichloromethane, acetonitrile, ethylene glycol dimethyl ether, diethoxymethane, dioxane, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, tetrahydrofuran, or 2-methyltetrahydrofuran.
5. The method for preparing the tetrahydrocurcumin intermediate as claimed in claim 4, wherein in the step b, when the catalyst is one or more of palladium carbon, palladium black, palladium hydroxide/carbon, platinum carbon or platinum oxide, the mass ratio of the content of palladium or platinum in the catalyst to the charging amount of the compound (II) is 0.001-0.5:1, preferably 0.005-0.2: 1; when the catalyst is Raney nickel, the mass ratio of the catalyst to the compound (II) is 0.001-0.5:1, preferably 0.005-0.2: 1.
6. The method for preparing tetrahydrocurcumin intermediate as claimed in claim 4, wherein in the step b, when the reducing agent is hydrogen, the reaction is carried out at 1 to 10 atm, preferably 1 to 3 atm.
7. The method for preparing tetrahydrocurcumin intermediate as claimed in claim 4, wherein in the step b, when the hydrogen donor is ammonium formate or formic acid/triethylamine, the feeding ratio of the reducing agent to the compound (II) is 1.8-8:1, preferably 1.8-5: 1; when the hydrogen donor is methanol, ethanol or isopropanol, the mass ratio of the hydrogen donor to the compound (II) is 1-100:1, preferably 1-10: 1; the reaction temperature is-78-150 ℃, and preferably-10-130 ℃; the reaction time is 0.5 to 36 hours, preferably 1 to 24 hours.
8. A process for producing tetrahydrocurcumin from the tetrahydrocurcumin intermediate as described in claims 1 to 7, characterized in that the compound (II) is deacetylated in a solvent in the presence of a base to obtain the compound (I), i.e., tetrahydrocurcumin, according to the following reaction scheme:
9. the method for preparing tetrahydrocurcumin as claimed in claim 6, wherein said base is one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, lithium hydroxide, sodium hydroxide, potassium hydroxide, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane, preferably one or more of sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide; the solvent is selected from benzene, toluene, chlorobenzene, xylene, isopropylbenzene, acetonitrile, benzonitrile, ethyl acetate, isopropyl acetate, 2-butanone, acetone, 1, 2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl ammonium phosphate, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, pyridine, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, t-butanol, t-amyl alcohol, polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-propylene glycol, diethoxymethane, dioxane, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane, cyclohexane, dichloromethane, toluene, ethyl acetate, isopropyl alcohol, ethylene glycol, t-butyl alcohol, t-amyl alcohol, One or more of 1, 2-dichloroethane, chloroform, or water; preferably one or more of methanol, ethanol, tetrahydrofuran or water.
10. The process for producing tetrahydrocurcumin as claimed in claim 6, wherein the equivalent ratio of said base to said compound (II) is 1.8 to 8:1, preferably 2 to 4: 1; the reaction temperature is selected from-10-150 ℃, and preferably 0-100 ℃; the reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.
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Cited By (2)
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|---|---|---|---|---|
| CN114031488A (en) * | 2021-11-05 | 2022-02-11 | 太阳树(莆田)生物医药有限公司 | Method for synthesizing tetrahydrocurcumin |
| CN117586111A (en) * | 2024-01-15 | 2024-02-23 | 天津泰普药品科技发展有限公司 | Method for preparing tetrahydrocurcumin through continuous catalytic hydrogenation |
-
2019
- 2019-12-21 CN CN201911331507.4A patent/CN111018705A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| ALEXANDER BARANOVSKY ET AL.,: ""Synthesis of New Biosynthetically Important Diarylheptanoids and Their Oxa- and Fluoro-Analogues by Three Different Strategies"", 《SYNTHETIC COMMUNICATIONS》 * |
| LOZADA, M. CONCEPCION ET AL.,: ""Synthesis and structure of new heterocyclic derivatives of curcumin"", 《HETEROCYCLES》 * |
| 姚其正主编: "《药物合成反应》", 30 September 2012, 中国医药科技出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114031488A (en) * | 2021-11-05 | 2022-02-11 | 太阳树(莆田)生物医药有限公司 | Method for synthesizing tetrahydrocurcumin |
| CN117586111A (en) * | 2024-01-15 | 2024-02-23 | 天津泰普药品科技发展有限公司 | Method for preparing tetrahydrocurcumin through continuous catalytic hydrogenation |
| CN117586111B (en) * | 2024-01-15 | 2024-03-19 | 天津泰普药品科技发展有限公司 | Method for preparing tetrahydrocurcumin through continuous catalytic hydrogenation |
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