A method for the synthesis of phloretin

Abstract

The application discloses a synthetic method of phloretin. The application provides a synthetic preparation method of a compound F, and key steps of the method include three steps: in the first step, acyl chlorination is carried out on cheap 3-(4-methoxyphenyl) propionic acid A to obtain C; in the second step, Friedel-Crafts acylation is carried out on C and D to obtain E; and in the third step, E is subjected to demethylation to obtain phloretin F. The path for synthesizing phloretin has a total reaction yield of up to 74%, can realize synthesis on a kilogram scale, is the most efficient and practical method so far, and provides an important foundation for synthetic biology research of phloretin. The method adopts a brand-new preparation process, and has the advantages of simple process, high yield and low cost.

Description

TECHNICAL FIELD

[0001] The present application relates to a synthetic method of phloretin, and belongs to the technical field of natural product synthesis. BACKGROUND

[0002] Phloretin is a naturally occurring dihydrochalcones plant polyphenol, which can be extracted from the peel and root bark of juicy fruits such as apples, grapefruits and pears. Recent studies have found that phloretin has antioxidant, immunosuppressive, hypoglycemic and other effects (Biochem Biophys Res Commun 2002, 295 (1): 9-13). The existing extraction process of phloretin is mainly aimed at natural substances containing phloretin, and high-purity phloretin is prepared by using acid hydrolysis, enzymatic hydrolysis and direct extraction method. Acid hydrolysis will cause serious environmental pollution due to the use of a large amount of acid solution; enzymatic hydrolysis is only effective for specific natural substances, and has a very limited scope, which is not suitable for industrial production; the phloretin obtained by direct extraction method is mostly in the form of glycoside, so the product yield is very low. In addition, phloretin can also be prepared by semi-synthesis from natural phlorizin, but the process is complex and not environmentally friendly.

[0003] In summary, the above-mentioned methods generally have the disadvantages of high cost, low operation efficiency and environmental pollution, and are not suitable for industrial production. Therefore, it is imperative to develop a highly efficient and full synthetic method of phloretin.

[0004] At present, there are few studies on the highly efficient and full synthesis of phloretin. In 2006, Vidavalur Siddaiah et al. synthesized phloretin from m-benzenetriol and hydroxyphenylpropionic acid as raw materials in the presence of BF3·Et2O as catalyst (Tetrahedron 2006, 62: 841-846), and the yield was only 30%; In 2010, Shi Lei et al. synthesized phloretin from 2'-hydroxy-4', 6'-bis(methoxymethoxy) acetophenone and p-methoxybenzaldehyde as raw materials by hydroxyaldehyde condensation, catalytic hydrogenation and dehydroxy protection (Chinese Journal of Pharmaceutical Chemistry 2010 (20): 176-180), and the yield was less than 40%. The above methods have low yield and poor practicability. Therefore, it is of high economic value and wide application value to develop a method for synthesizing phloretin with higher yield and better practicability. SUMMARY

[0005] The problem to be solved by the present application is to overcome the single organic synthesis route and low reaction yield of the prior art, and to provide a synthetic method of phloretin. The present application adopts a new preparation process, which is simple, high-yield and low-cost.

[0006] The application provides a preparation method of compound E, which comprises the following steps: performing acylation reaction on compound C and compound D in an organic solvent in the presence of aluminum chloride to obtain the compound E.

[0007]

[0008] R is C1-C4 alkyl.

[0009] In an embodiment of the application, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0010] In an embodiment of the application, the organic solvent can be conventional for such reactions in the art, for example, a chlorine-containing organic solvent, preferably dichloromethane.

[0011] In an embodiment of the application, the reaction temperature of the preparation method of the compound E can be conventional for such reactions in the art, for example, -10-10 ℃, preferably 0 ℃.

[0012] In an embodiment of the application, the molar ratio of the compound D to the compound C can be conventional for such reactions in the art, for example, 1:1-5:1.

[0013] In an embodiment of the application, the molar ratio of the aluminum chloride to the compound D can be conventional for such reactions in the art, for example, 1:1-3:1, for example, 1:1, 2:1 or 3:1, preferably 1:1.

[0014] In an embodiment of the application, the mass-volume ratio of the compound C to the organic solvent can be conventional for such reactions in the art, for example, 70-120 g / L, preferably 110.5 g / L.

[0015] In an embodiment of the application, the temperature of the acylation reaction can be conventional for such reactions in the art, for example, 20-50 ℃, preferably 25 ℃.

[0016] In an embodiment of the application, the reaction time of the acylation reaction is not reduced based on the amount of compound C, and the reaction time can be 1-5 hours, preferably 3 hours.

[0017] In an embodiment of the application, the acylation reaction further comprises a post-treatment step, and the post-treatment can be conventional for such reactions in the art, for example, extraction, washing, concentration, beating, filtration, drying or silica gel column purification, preferably dichloromethane extraction, saturated brine washing, anhydrous magnesium sulfate drying, filtration, concentration, silica gel column chromatography purification (petroleum ether: ethyl acetate = 4:1).

[0018] The preparation method of the compound E can further comprise the following step: performing acylation reaction on compound A and compound B in an organic solvent to obtain the compound C.

[0019]

[0020] In an embodiment of the present application, the organic solvent can be one or more of conventional organic solvents for such reaction in the art, for example, one or more of chlorine-containing organic solvents and nitrogen-containing organic solvents, preferably dichloromethane and N,N-dimethylformamide.

[0021] In an embodiment of the present application, the temperature of the reactants for the preparation method of the compound A can be conventional for such reaction in the art, for example, -10-10°C, preferably 0°C.

[0022] In an embodiment of the present application, the molar ratio of the compound B to the compound A can be conventional for such reaction in the art, for example, 1:1-5:1, for example, 2:1.

[0023] In an embodiment of the present application, the molar volume ratio of the compound A to the chlorine-containing organic solvent can be conventional for such reaction in the art, for example, 0.2-1.0 mol / L, preferably 0.4 mol / L.

[0024] In an embodiment of the present application, the molar volume ratio of the compound A to the nitrogen-containing organic solvent can be conventional for such reaction in the art, for example, 0.2-1.0 mol / L, preferably 0.5 mol / L.

[0025] In an embodiment of the present application, the temperature of the acylation reaction can be conventional for such reaction in the art, for example, 20-50°C, preferably 25°C.

[0026] In an embodiment of the present application, the reaction time of the acylation reaction can be 1-5 hours, preferably 2 hours, provided that the amount of the compound C is not reduced.

[0027] The present application further provides a preparation method of phloretin, which comprises the following steps: performing deprotection reaction on compound E and BBr3 in an organic solvent to obtain the phloretin.

[0028]

[0029] In the formula, R is C1-C4 alkyl.

[0030] In an embodiment of the present application, the C1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0031] In an embodiment of the present application, the organic solvent can be conventional for such reactions in the art, for example, a chlorinated organic solvent, preferably dichloroethane.

[0032] In an embodiment of the present application, the temperature of the reactants for the preparation of phloretin can be conventional for such reactions in the art, for example, -10 to 10°C, preferably 0°C.

[0033] In an embodiment of the present application, the molar ratio of BBr3 to the compound E can be conventional for such reactions in the art, for example, 3:1 to 7:1, for example, 4.5:1, 5.5:1 or 7:1, preferably 5.5:1.

[0034] In an embodiment of the present application, the molar volume ratio of the compound E to the organic solvent can be conventional for such reactions in the art, for example, 0.2 to 0.8 g / L, preferably 0.47 mol / L.

[0035] In an embodiment of the present application, the temperature of the deprotection reaction can be conventional for such reactions in the art, for example, 40 to 80°C, for example, 40°C, 60°C or 80°C, preferably 60°C.

[0036] In an embodiment of the present application, the reaction time of the deprotection reaction can be 1 to 5 hours, preferably 3 hours, based on the amount of compound C.

[0037] In an embodiment of the present application, the deprotection reaction further comprises a post-treatment step, which can be conventional for such reactions in the art, for example, concentration or silica gel column purification, preferably methanol quenching, concentration, silica gel column chromatography purification (dichloromethane:methanol = 9:1).

[0038] In an embodiment of the present application, the preparation of phloretin in the deprotection reaction can be as described above.

[0039] The present application provides a preparation method of compound C, which comprises the following steps: acylating compound A with compound B in an organic solvent to obtain the compound C.

[0040]

[0041] In an embodiment of the present application, the acylation reaction conditions are as described above.

[0042] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, thereby obtaining each preferred example of the present application.

[0043] The reagents and raw materials used in the present application are commercially available.

[0044] The positive progress effect of the present application is to provide a synthetic method of phloretin. The method adopts a brand-new preparation process, and has simple process, high yield and low cost. DETAILED DESCRIPTION

[0045] The present application is further illustrated by the following examples without limiting the present application to the examples described. The experimental methods in the following examples without specific conditions are selected according to the conventional methods and conditions or the product instructions.

[0046] Example 1

[0047] This example takes the preparation of 3-(4-methoxyphenyl)propionyl chloride (its reaction route is shown below) as an example to illustrate in detail the method for preparing the phloretin intermediate according to the present application:

[0048]

[0049] Under nitrogen protection, 3-(4-methoxyphenyl)propionic acid (1.955 g, 10.85 mmol) and 25 ml of dichloromethane were added to a 100 ml round-bottom flask in an ice water bath, and oxalyl chloride (1.8 ml, 21.7 mmol), N,N-dimethylformamide (0.08 ml, 1.085 mmol) were added to the stirred solution. Stirring was performed at room temperature (25°C) for 2 h. After the reaction was completed, the product was concentrated under reduced pressure to obtain a yellow viscous liquid 3-(4-methoxyphenyl)propionyl chloride 2.10 g, with a yield of 97.4% and a product nuclear magnetic purity of >99%. The obtained product was directly used in the next step.

[0050] Example 2

[0051]

[0052] Under nitrogen protection, 3-(4-methoxyphenyl)propionyl chloride obtained in the previous step was added to 19 ml of dichloromethane in an ice water bath, and the acyl chloride substrate was completely dissolved under stirring. Then 1,3,5-trimethoxybenzene (1.825 g, 10.85 mmol) was added, and after it was completely dissolved, anhydrous aluminum chloride (1.469 g, 11 mmol) was added, and it was completely dissolved under stirring. Stirring was performed at room temperature (25°C) for 3 h. After the reaction was completed, the reaction was quenched with water, and the organic phase was extracted with dichloromethane, and the operation was repeated three times, then the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a light yellow-green oily liquid 3-(4-methoxyphenyl)-1-(2,4,6-trimethoxyphenyl)propan-1-one 3.35 g, with a yield of 95.9% and a product nuclear magnetic purity of >99%.

[0053] 1 H NMR (500 MHz, CDC13) δ 7.15 - 7.10 (m, 2H), 6.85 - 6.79 (m, 2H), 6.09 (s, 2H), 3.84 - 3.77 (m, 6H), 3.75 (s, 6H), 3.06 - 2.98 (m, 2H), 2.94 (d, J = 8.1 Hz, 2H).

[0054] 13 C NMR (126 MHz, CDC13) δ 203.81, 162.36, 158.31, 157.85, 133.75, 129.41, 114.04, 113.80, 113.49, 90.66, 55.88, 55.53, 55.37, 46.69, 29.21.

[0055] Other conditions correspond, the kind of Lewis acid and the molar ratio of Lewis acid to compound D in the reaction are screened, to prepare compound E, and the yield is shown in Table 1.

[0056] Table 1 Lewis acid and molar ratio of Lewis acid to compound D condition screening

[0057] No. Lewis acid Molar ratio of Lewis acid to compound D Yield 1 AlCl3 0.5 2 AlCl3 0.5 3 AlCl3 0.5 4 AlCl3 0. 1 BCl3 1:1 47.6％ 2 FeCl3 1:1 54.3％ 3 AlCl3 1:1 95.9％ 4 AlCl3 2:1 82.1％ 5 AlCl3 3:1 77.5％

[0058] Example 3

[0059]

[0060] Into a 25 ml vial was placed 3-(4-methoxyphenyl)-l-(2,4,6-trimethoxyphenyl)propan-l-one (0.200 g, 0.605 mmol) followed by 1.3 ml dichloroethane to completely dissolve the substrate under stirring. Boron tribromide (0.32 ml, 3.328 mmol) was added dropwise into the reaction vial under ice water bath condition, and stirred at 60 °C for 3 h. After the reaction was completed, the reaction was quenched with methanol, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 19:1) to give 3-(4-hydroxyphenyl)-l-(2,4,6-trihydroxyphenyl)propan-l-one 0.133 g in 80.1% yield, product NMR purity >99%.

[0061] 1 H NMR (500 MHz, DMSO) δ 12.29 (s, 2H), 10.39 (s, 1H), 9.18 (s, 1H), 7.06 (d, J = 7.9 Hz, 2H), 6.70 (d, J = 7.8 Hz, 2H), 5.85 (s, 2H), 3.29 - 3.20 (m, 2H), 2.83 - 2.75 (m, 2H).

[0062] 13 C NMR (126 MHz, DMSO) δ 204.35, 164.73, 164.36, 155.52, 131.79, 129.31, 115.20, 103.86, 94.80, 45.63, 29.57.

[0063] Other conditions correspond, the corresponding to the kind of deprotection reagent in this step reaction, Lewis acid and compound E and the molar ratio of reaction temperature condition screening, preparation of phloretin, its yield as shown in table 2.

[0064] Table 2 the kind of deprotection reagent, Lewis acid and compound E and the molar ratio of reaction temperature condition screening

[0065]

Claims

1. A method for preparing phlorizin, comprising the following steps: in an organic solvent, compound E is subjected to a deprotection reaction with BBr3, followed by post-treatment to obtain the phlorizin; R is a C1 alkyl group; The organic solvent is dichloroethane; The temperature for the deprotection reaction is 40~80℃; The deprotection reaction takes 1 to 5 hours. The post-processing involves methanol quenching, concentration, and silica gel column chromatography purification, with the eluent for silica gel column chromatography being dichloromethane:methanol = 19:

1. The preparation method of compound E includes the following steps: in an organic solvent, in the presence of aluminum trichloride, compound C and compound D are subjected to an acylation reaction to obtain compound E; The acylation reaction was performed at a temperature of 25°C. The acylation reaction takes 1 to 5 hours. The acylation reaction includes a post-processing step, which is dichloromethane extraction, washing with saturated brine, drying with anhydrous magnesium sulfate, filtration, concentration, and silica gel column chromatography purification. In the preparation method of compound E, the eluent for silica gel column chromatography purification is petroleum ether: ethyl acetate = 4:

1. The preparation method of compound C includes the following steps: in an organic solvent, compound A and compound B are subjected to an acylation reaction to obtain compound C; 。 2. The preparation method according to claim 1, characterized in that, The preparation method of compound E satisfies one or more of the following conditions: (1) The organic solvent is a chlorine-containing organic solvent; (2) The reaction material feeding temperature in the preparation method of compound E is -10~10℃; (3) The molar ratio of compound D to compound C is 1:1 to 5:1; (4) The molar ratio of aluminum trichloride to compound D is 1:1 to 3:1; (5) The mass-volume ratio of compound C to organic solvent is 70~120 g / L.

3. The preparation method according to claim 2, characterized in that, The preparation method of compound E satisfies one or more of the following conditions: (1) The organic solvent is dichloromethane; (2) The reaction material feeding temperature in the preparation method of compound E is 0℃; (3) The molar ratio of aluminum trichloride to compound D is 1:1, 2:1 or 3:1; (4) The mass-to-volume ratio of compound C to the organic solvent is 110.5 g / L.

4. The preparation method according to claim 1, characterized in that, The preparation method of compound C satisfies one or more of the following conditions: (1) The organic solvent is one or more of chlorine-containing organic solvents and nitrogen-containing organic solvents; (2) The reaction material feeding temperature in the preparation method of compound C is -10~10℃; (3) The molar ratio of compound B to compound A is 1:1 to 5:1; (4) The molar volume ratio of compound A to the chlorine-containing organic solvent is 0.2~1.0 mol / L; (5) The molar volume ratio of compound A to the nitrogen-containing organic solvent is 0.2~1.0 mol / L; (6) The temperature of the acylation reaction is 20~50℃; (7) The reaction time of the acylation reaction is 1 to 5 hours.

5. The preparation method according to claim 1, characterized in that, Deprotection reactions satisfy one or more of the following conditions: (1) The reaction material feeding temperature in the preparation method of phloretin is -10~10℃; (2) The molar ratio of BBr3 to compound E is 3:1 to 7:1; (3) The molar volume ratio of compound E to organic solvent is 0.2~0.8 mol / L.

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