A preparation method of shikonin

Abstract

The present invention discloses a preparation method of shikonin deoxysulfate, and the synthesis is carried out by adopting the following technological route:

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for preparing deoxyshikonin. Background Art

[0002] Deoxyshikonin is a natural plant pigment, which has various pharmacological activities such as antioxidant, antibacterial, anti-inflammatory and anti-tumor, and is expected to become the first choice drug for humans to treat various cancers and special diseases. It has now been applied in the fields of food, medicine, cosmetics, etc., and has a very broad future development prospect.

[0003] In the prior art, due to the complexity and particularity of the molecular structure of deoxyshikonin, the chemical total synthesis process is challenging. Therefore, the main current way to obtain deoxyshikonin is to extract it from the roots of the natural plant Lithospermum erythrorhizon. However, because the content of deoxyshikonin in natural plants is not high itself, it is not easy to purify, and the difficulty of large-scale production is high, resulting in its high price. This not only limits the production of deoxyshikonin, but also greatly restricts the further pharmacological research and the development of its applications. Summary of the Invention

[0004] Aiming at the above deficiencies existing in the prior art, the purpose of the present invention is to provide a method for preparing deoxyshikonin to solve the problems that deoxyshikonin in the prior art can only be obtained by extraction from natural plants, and has high purification difficulty and high large-scale production difficulty.

[0005] To solve the above technical problems, the present invention adopts the following technical scheme:

[0006] A method for preparing deoxyshikonin is synthesized by adopting the following process route:

[0007]

[0008] Preferably, it specifically includes the following steps:

[0009] Step 1: Compound 1 reacts with ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate under an alkaline condition to obtain Compound 2 through the Horner-Wadsworth-Emmons reaction;

[0010] Step 2: Compound 2 undergoes a hydrolysis reaction under an alkaline condition to generate Compound 3;

[0011] Step 3: Compound 3 reacts with one of trifluoroacetic anhydride, boron trifluoride dimethyl ether or pyrophosphoryl chloride to carry out intramolecular cyclization to obtain Compound 4;

[0012] Step 4: Compound 4 undergoes an oxidation reaction under the action of an oxidant to obtain Compound 5;

[0013] Step 5: Compound 5 undergoes a dehydroxy protection reaction with boron tribromide to obtain compound 6, deoxyshikonin.

[0014] Preferably, in Step 1, the reaction temperature is -80°C to -70°C; the alkaline environment is obtained by potassium tert-butoxide or sodium hydride; when the alkaline environment is obtained by potassium tert-butoxide, the molar ratio of compound 1, ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate to potassium tert-butoxide is 1:(1 - 1.3):(1.1 - 1.4); when the alkaline environment is obtained by sodium hydride, the molar ratio of compound 1, ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate to sodium hydride is 1:(1 - 1.3):(1.1 - 1.4); toluene or tetrahydrofuran is used as the solvent.

[0015] Preferably, in Step 2, the reaction temperature is 65 - 75°C; the alkaline environment is obtained by potassium carbonate or lithium hydroxide; when the alkaline environment is obtained by potassium carbonate, the molar ratio of compound 2 to potassium carbonate is 1:(8 - 10); when the alkaline environment is obtained by lithium hydroxide, the molar ratio of compound 2 to lithium hydroxide is 1:(8 - 10); methanol or ethanol is used as the solvent.

[0016] Preferably, in Step 3, when compound 3 reacts with trifluoroacetic anhydride, the reaction temperature is 0°C, and the molar ratio of compound 3 to trifluoroacetic anhydride is 1:(2 - 4); when compound 3 reacts with boron trifluoride dimethyl ether, the reaction temperature is 125 - 130°C, and the molar ratio of compound 3 to boron trifluoride dimethyl ether is 1:(9 - 11); when compound 3 reacts with pyrophosphoryl chloride, the reaction temperature is room temperature, and the molar ratio of compound 3 to pyrophosphoryl chloride is 1:(9 - 11).

[0017] Preferably, in Step 4, the oxidant is (diacetoxyiodo)benzene, tert-butyl hydroperoxide or ammonium cerium nitrate; among them, when the oxidant is (diacetoxyiodo)benzene, the molar ratio of compound 4 to (diacetoxyiodo)benzene is 1:(1.5 - 3); when the oxidant is tert-butyl hydroperoxide, the molar ratio of compound 4 to tert-butyl hydroperoxide is 1:(8 - 10); when the oxidant is ammonium cerium nitrate, the molar ratio of compound 4 to ammonium cerium nitrate is 1:(3 - 5); the reaction solvent is one of acetonitrile, acetone or tetrahydrofuran; the reaction temperature is room temperature.

[0018] Preferably, in Step 5, dichloromethane is used as the solvent, the reaction temperature is 0°C, and the molar ratio of compound 5 to boron tribromide is 1:(3 - 5).

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] The present invention has conducted in-depth research and selection on the organic synthesis route, and innovatively designed a controllable, sustainable and more cost-effective chemical synthesis process route for producing shikonin. Generally speaking, this route is relatively short, reasonably designed, with inexpensive and easily available raw materials, simple operation, easy to control, and without overly harsh reaction conditions in the overall process. It is a relatively efficient, economical, safe, green and environmentally friendly chemical total synthesis process route, having good industrial application prospects. Detailed implementation manners

[0021] The present invention will, in combination with the embodiments of the present invention, clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the present invention belong to the scope of protection of the present invention.

[0022] Unless otherwise specified in specific circumstances in the present invention, the numerical ranges listed in the present invention include the upper and lower limit values, as well as all integers and fractions within this range, rather than the specific values listed when defining the range.

[0023] I. A preparation method of shikonin

[0024]

[0025] The present invention has conducted in-depth research and selection on the organic synthesis route, and innovatively designed a controllable, sustainable and more cost-effective process route for producing shikonin. Generally speaking, this route is relatively short, reasonably designed, with inexpensive and easily available raw materials, simple operation, easy to control, and without overly harsh reaction conditions in the overall process. It is a relatively efficient, economical, safe, green and environmentally friendly chemical total synthesis process route.

[0026] In some embodiments, it specifically includes the following steps:

[0027] Step 1: 2-(2,5-Dimethoxyphenyl)acetaldehyde (Compound 1) reacts with ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate under a basic condition in a Horner-Wadsworth-Emmons reaction (HWE reaction) to obtain ethyl (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoate (Compound 2). In specific implementation, the reaction temperature is -80 °C to -70 °C, and all ranges and sub-ranges between the above values. The basic condition is obtained by potassium tert-butoxide or sodium hydride. When potassium tert-butoxide is used, the molar ratio of Compound 1, ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate and potassium tert-butoxide is 1:(1 - 1.3):(1.1 - 1.4), and can further be 1:1:1.1, 1:1.1:1.2, 1:1.2:1.3, 1:1.3:1.4, etc., and all ranges and sub-ranges between the above values. When sodium hydride is used, the molar ratio of Compound 1, ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate and sodium hydride is 1:(1 - 1.3):(1.1 - 1.4), and can further be 1:1:1.1, 1:1.1:1.2, 1:1.2:1.3, 1:1.3:1.4, etc., and all ranges and sub-ranges between the above values. Toluene or tetrahydrofuran is used as the solvent in this reaction process. It should be understood that in the embodiments, any of the above ranges can be combined with any other range.

[0028] Step 2: Ethyl (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoate (Compound 2) undergoes a hydrolysis reaction under a basic condition to generate (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoic acid (Compound 3). In specific implementation, the reaction temperature is 65 - 75 °C, and all ranges and sub-ranges between the above values. The basic condition is obtained by potassium carbonate or lithium hydroxide. When the basic condition is obtained by potassium carbonate, the molar ratio of Compound 2 and potassium carbonate is 1:(8 - 10), and can further be 1:8, 1:9, 1:10, etc., and all ranges and sub-ranges between the above values. When the basic condition is obtained by lithium hydroxide, the molar ratio of Compound 2 and lithium hydroxide is 1:(8 - 10), and can further be 1:8, 1:9, 1:10, etc., and all ranges and sub-ranges between the above values. Methanol or ethanol is used as the solvent in this reaction process. It should be understood that in the embodiments, any of the above ranges can be combined with any other range.

[0029] Step 3: (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoic acid (Compound 3) reacts with trifluoroacetic anhydride (TFAA), boron trifluoride dimethyl ether or phosphorus oxychloride to carry out intramolecular cyclization to obtain 5,8-dimethoxy-2-(4-methyl-3-en-1-yl)naphthalen-1(4H)-one (Compound 4). In specific implementation, according to the differences in raw materials, the conditions for the intramolecular cyclization reaction will vary. When Compound 3 reacts with trifluoroacetic anhydride, the reaction temperature is 0 °C, and the molar ratio of Compound 3 to trifluoroacetic anhydride is 1:(2 - 4), which can be further 1:2, 1:2.5, 1:3, 1:3.5, 1:4, etc., as well as all ranges and sub-ranges between the above values. When Compound 3 reacts with boron trifluoride dimethyl ether, the reaction temperature is 125 - 130 °C, and the molar ratio of Compound 3 to boron trifluoride dimethyl ether is 1:(9 - 11), which can be further 1:9, 1:10, 1:11, etc., as well as all ranges and sub-ranges between the above values. When Compound 3 reacts with phosphorus oxychloride, the reaction temperature is room temperature, and the molar ratio of Compound 3 to phosphorus oxychloride is 1:(9 - 11), which can be further 1:9, 1:10, 1:11, etc., as well as all ranges and sub-ranges between the above values. It should be understood that in the implementation scheme, any of the above ranges can be combined with any other range.

[0030] Step 4: 5,8-dimethoxy-2-(4-methyl-3-en-1-yl)naphthalen-1(4H)-one (Compound 4) undergoes an oxidation reaction under the action of an oxidant to obtain 5,8-dimethoxy-2-(4-methyl-3-en-1-yl)naphthalene-1,4-dione (Compound 5). In specific implementation, the type of oxidant will affect its dosage. The oxidant is (diacetoxyiodo)benzene, tert-butyl hydroperoxide or ammonium cerium nitrate. Among them, when the oxidant is (diacetoxyiodo)benzene, the molar ratio of Compound 4 to (diacetoxyiodo)benzene is 1:(1.5 - 3), which can be further 1:1.5, 1:2.0, 1:2.5, 1:3.0, etc., as well as all ranges and sub-ranges between the above values. When the oxidant is tert-butyl hydroperoxide, the molar ratio of Compound 4 to tert-butyl hydroperoxide is 1:(8 - 10), which can be further 1:8, 1:9, 1:10, etc., as well as all ranges and sub-ranges between the above values. When the oxidant is ammonium cerium nitrate, the molar ratio of Compound 4 to ammonium cerium nitrate is 1:(3 - 5), which can be further 1:3, 1:3.5, 1:4, 1:4.5, 1:5, etc., as well as all ranges and sub-ranges between the above values. In this reaction process, the reaction solvent is one of acetonitrile, acetone or tetrahydrofuran. This reaction process is carried out at room temperature. It should be understood that in the implementation scheme, any of the above ranges can be combined with any other range.

[0031] Step 5: 5,8-Dimethoxy-2-(4-methyl-3-en-1-yl)naphthalene-1,4-dione (Compound 5) undergoes a dehydroxy protection reaction with boron tribromide to obtain 5,8-dihydroxy-2-(4-methyl-3-en-1-yl)naphthalene-1,4-dione (Compound 6), which is the final product shikonin. In specific implementation, dichloromethane is used as the solvent, the reaction temperature is 0 °C, and the molar ratio of Compound 5 to boron tribromide is 1:(3 - 5), which can further be 1:3, 1:4, 1:5, etc., as well as all ranges and sub-ranges between the above values. It should be understood that in the implementation examples, any of the above ranges can be combined with any other range.

[0032] II. Examples

[0033] (1) Synthesis of Ethyl (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoate (Compound 2)

[0034] Example 1: At room temperature, dissolve ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate (2.585 g, 8.438 mmol) in 10 mL of toluene, add potassium tert-butoxide (1.031 g, 9.188 mmol), and continuously stir until potassium tert-butoxide is completely dissolved; cool the system to -78 °C, dissolve 2-(2,5-dimethoxyphenyl)acetaldehyde (Compound 1) (1.382 g, 7.669 mmol) in 10 mL of toluene solution and transfer it to a constant pressure dropping funnel, and slowly drop it in; after dropping, continue the reaction at -78 °C for 12 h. After the reaction is completed, add a saturated NH4Cl aqueous solution to quench the reaction, extract the aqueous phase with ethyl acetate (30 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure, and purify by column chromatography to obtain 1.621 g of a colorless transparent oil, with a yield of 63.6% and a purity of 96%.

[0035] 1 1H-NMR shows that a pair of cis-trans isomers are obtained in the reaction, the cis product is the target product, and the amount of the cis product: the amount of the trans product is = 1:2.5.

[0036] Example 2: At room temperature, ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate (2.609 g, 8.517 mmol) was dissolved in 10 mL of toluene, and sodium hydride with a mass content of 60% (0.372 g, 9.289 mmol) was added and stirred continuously until the sodium hydride was completely dissolved; the system was cooled to -78 °C, 2-(2,5-dimethoxyphenyl)acetaldehyde (Compound 1) (1.395 g, 7.741 mmol) was dissolved in 10 mL of toluene solution and transferred to a constant pressure dropping funnel, and it was slowly dropped in; after dropping, the reaction was continued at -78 °C for 12 h. After the reaction was completed, the reaction was quenched by adding a saturated NH4Cl aqueous solution, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography analysis to obtain 1.595 g of a colorless transparent oil, with a yield of 62.0% and a purity of 95%.

[0037] 1 1H-NMR indicated that a pair of cis-trans isomers were obtained in the reaction, the cis product was the target product, and the amount of the cis product: the amount of the trans product was = 1:2.5.

[0038] 1 H NMR (600 MHz, CDCl3) δ 6.86 (t, J = 7.8 Hz, 1H, E), 6.80–6.79 (m, 0.4×1H, Z), 6.78–6.77 (m, 1H, E), 6.75–6.74 (m, 0.4×2H, Z), 6.73–6.71 (m, 2H, E), 5.97 (t, J = 7.2 Hz, 0.4×1H, Z), 5.21–5.17 (m, 1H, E), 5.11–5.08 (m, 0.4×1H, Z), 4.25 (q, J = 7.2 Hz, 0.4×2H, Z), 4.19 (q, J = 7.2 Hz, 2H, E), 3.80 (s, 3H, E), 3.78 (s, 0.4×3H, Z), 3.77 (s, 3H, E), 3.76 (s, 0.4×3H, Z), 3.74 (d, J = 7.8 Hz, 0.4×2H, Z), 3.50 (d, J = 7.8 Hz, 2H, E), 2.47–2.42 (m, 2H, E), 2.30–2.26 (m, 0.4×2H, Z), 2.18–2.14 (m, 2H, E), 2.12–2.09 (m, 0.4×2H, Z), 1.69 (d, J = 0.6 Hz, 3H, E), 1.66 (d, J = 0.6 Hz, 0.4×3H, Z), 1.62 (s, 3H, E), 1.58 (s, 0.4×3H, Z), 1.33 (t, J = 7.2 Hz, 0.4×3H, Z), 1.29 (t, J = 7.2 Hz, 3H, E).

[0039] 13 13C NMR (151 MHz, CDCl3) δ 167.97 (s), 153.54 (s), 151.61 (s), 140.29 (s), 132.67 (s), 132.28 (s), 128.72 (s), 123.76 (s), 116.36 (s), 111.28 (d, J = 27.1 Hz), 60.38 (s), 55.92 (s), 55.72 (s), 34.80 (s), 30.39 (s), 29.26 (s), 27.80 (s), 25.73 (s), 17.65 (s), 14.32 (s). MS (ESI): m / z 333.20 (M+H + ).

[0040] (2) Synthesis of (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoic acid (Compound 3)

[0041] Example 3: At room temperature, ethyl (E)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoate and ethyl (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoate (Compound 2) (1.621 g in total, 4.876 mmol) which could not be separated were co-dissolved in 15 mL of methanol. K2CO3 (6.065 g, 43.882 mmol) and 15 mL of H2O were added. Then the mixture was refluxed under Ar protection for 5 hours. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure. Saturated aqueous NH4Cl solution was added to the mixture for neutralization. The aqueous phase was extracted with diethyl ether (30 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography analysis to obtain 0.370 g of (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoic acid (Compound 3) as a colorless oil, with a yield of 87.3% [relative to the cis raw material] and a purity of 97%.

[0042] Example 4: At room temperature, ethyl (E)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoate and ethyl (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoate (Compound 2) (1.595 g in total, 4.798 mmol) were co-dissolved in 15 mL of methanol. Lithium hydroxide monohydrate (1.812 g, 43.184 mmol) and 15 mL of H2O were added, and then the reaction was refluxed for 5 hours under Ar protection. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure. The mixture was neutralized with saturated aqueous NH4Cl solution, and the aqueous phase was extracted with diethyl ether (30 mL × 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography analysis to obtain 0.346 g of colorless oily (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoic acid (Compound 3), with a yield of 82.9% [relative to the cis raw material] and a purity of 96%.

[0043] The products of Examples 3 - 4 were detected, and the MS (ESI) of the obtained colorless oily substance: m / z 305.17 (M+H + ).

[0044] (3) Synthesis of 5,8-dimethoxy-2-(4-methyl-3-en-1-yl)naphthalen-1(4H)-one (Compound 4)

[0045] Example 5: At room temperature, (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoic acid (Compound 3) (0.370 g, 1.216 mmol) was dissolved in 8 mL of dichloromethane. The system was cooled to 0 °C, trifluoroacetic anhydride (0.507 mL, 3.684 mmol) was added, and the reaction was continued at 0 °C for 1 hour. After the reaction was completed, saturated NaHCO3 was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography analysis to obtain 0.274 g of pale yellow transparent oily substance, with a yield of 78.7% and a purity of 97%.

[0046] Example 6: (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoic acid (Compound 3) (0.346 g, 1.137 mmol) and boron trifluoride dimethyl ether (1.045 mL, 11.370 mmol) were refluxed at 127 °C for 3 hours. After the reaction was completed, 20 mL of H2O was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography analysis to obtain 0.229 g of pale yellow transparent oily substance, with a yield of 70.3% and a purity of 97%.

[0047] Example 7: Under Ar protection, (Z)-2-(2,5-dimethoxyphenyl)ethylidene)-6-methylhept-5-enoic acid (Compound 3) (0.341 g, 1.120 mmol) and phosphoryl chloride (1.549 mL, 11.200 mmol) were stirred at room temperature for 3 hours. After the reaction was completed, the excess phosphoryl chloride was removed by direct distillation under reduced pressure. Then, it was purified by column chromatography analysis to obtain 0.206 g of a pale yellow transparent oil, with a yield of 64.2% and a purity of 96%.

[0048] The products of Examples 5-7 were detected, and the MS (ESI) of the obtained pale yellow transparent oil: m / z 287.16 (M+H + ).

[0049] (4) Synthesis of 5,8-dimethoxy-2-(4-methyl-3-en-1-yl)naphthalene-1,4-dione (Compound 5)

[0050] Example 8: At room temperature, 5,8-dimethoxy-2-(4-methyl-3-en-1-yl)naphthalen-1(4H)-one (Compound 4) (0.274 g, 0.957 mmol) was dissolved in 8 mL of acetonitrile, H2O (4 mL) and (diacetoxyiodo)benzene (DIB) (0.616 g, 1.914 mmol) were added, and the system was stirred at room temperature for 1 hour. After the reaction was completed, it was diluted with water, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and then purified by column chromatography analysis to obtain 0.196 g of a colorless transparent oil, with a yield of 68.2% and a purity of 96%.

[0051] Example 9: At room temperature, 5,8-dimethoxy-2-(4-methyl-3-en-1-yl)naphthalen-1(4H)-one (Compound 4) (0.229 g, 0.800 mmol), tert-butyl hydroperoxide (0.769 mL, 8.000 mmol) and cobalt(II) acetylacetonate (0.0207 g, 0.080 mmol) were dissolved in 8 mL of acetone, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, 10 mL of H2O was added, and the aqueous phase was extracted with ethyl acetate (20 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and then purified by column chromatography analysis to obtain 0.156 g of a colorless transparent oil, with a yield of 65.0% and a purity of 96%.

[0052] Example 10: At room temperature, 5,8-dimethoxy-2-(4-methyl-3-en-1-yl)naphthalen-1(4H)-one (Compound 4) (0.224 g, 0.782 mmol) and ammonium cerium(IV) nitrate (1.715 g, 3.128 mmol) were dissolved in 8 mL of acetone and 2 mL of H2O, and the mixture was stirred at room temperature for 14 h. After the reaction was completed, the aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 0.142 g of a colorless transparent oil, with a yield of 60.4% and a purity of 96%.

[0053] The products of Examples 8 - 10 were detected, and the MS (ESI) of the obtained colorless transparent oil: m / z 301.14 (M+H + ).

[0054] (5) Synthesis of 5,8-dihydroxy-2-(4-methyl-3-en-1-yl)naphthalene-1,4-dione (Compound 6)

[0055] At room temperature, 5,8-dimethoxy-2-(4-methyl-3-en-1-yl)naphthalen-1(4H)-one (Compound 5) (0.187 g, 0.623 mmol) was dissolved in 8 mL of dichloromethane. The system was cooled to -78 °C, and a dichloromethane solution of BBr3 (1.869 mL, 1.869 mmol) was added. Then, the mixture was stirred at 0 °C for 1 h, H2O (4 mL) was added and stirring was continued for 30 min. After the reaction was completed, the mixture was diluted with water, and the aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 0.116 g of a colorless transparent oil, with a yield of 68.4% and a purity of 97%.

[0056] The obtained colorless transparent oil was detected, and the results were as follows:

[0057] IR v max (CHC13) cm -1 : 3450 (OH), 1620 (C=O), 1520 (C=C).

[0058] EI-MS m / z: 273.10 [M+H + .

[0059] 11H NMR (600 MHz, CDCl3) δ 12.63 (s, 1H), 12.47 (s, 1H), 7.21 (s, 1H), 6.85 (s, 1H), 5.15 (t, J = 7.3 Hz, 1H), 2.63 (t, J = 7.3 Hz, 2H), 2.31 (q, J = 7.3 Hz, 2H), 1.69 (d, J = 1.5 Hz, 3H), 1.60 (s, 3H).

[0060] 13 13C NMR (151 MHz, CDCl3) δ 183.10 (s), 183.04 (s), 162.88 (s), 162.21 (s), 151.49 (s), 134.55 (d), 133.61 (s), 131.15 (d), 130.82 (d), 122.29 (d), 111.96 (s), 111.69 (s), 29.70 (t), 26.54 (t), 25.66 (q), 17.80 (q), 25.73 (s).

[0061] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit them. Those of ordinary skill in the art should understand that any modifications or equivalent replacements made to the technical solutions of the present invention without departing from the purpose and scope of the present technical solution shall be covered by the scope of the claims of the present invention.

Claims

1. A preparation method of shikonin, characterized in that, The synthesis is carried out using the following process route: Specifically, it includes the following steps: Step 1: Compound 1 reacts with ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate under a basic environment to undergo the Horner-Wadsworth-Emmons reaction, yielding Compound 2; Step 2: Compound 2 undergoes a hydrolysis reaction under a basic environment to generate Compound 3; Step 3: Compound 3 reacts with one of trifluoroacetic anhydride, boron trifluoride dimethyl ether, or pyrophosphoryl chloride to carry out an intramolecular cyclization, obtaining Compound 4; Step 4: Compound 4 undergoes an oxidation reaction under the action of an oxidizing agent to obtain Compound 5; Step 5: Compound 5 undergoes a dehydroxylation protection reaction with boron tribromide to obtain Compound 6, deoxyshikonin.

2. The preparation method of deoxyshikonin according to claim 1, characterized in that, In Step 1, the reaction temperature is -80°C to -70°C; the basic environment is obtained by potassium tert-butoxide or sodium hydride; when the basic environment is obtained by potassium tert-butoxide, the molar ratio of Compound 1, ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate, and potassium tert-butoxide is 1:(1 - 1.3):(1.1 - 1.4); when the basic environment is obtained by sodium hydride, the molar ratio of Compound 1, ethyl 2-(diethoxyphosphoryl)-6-methylhept-5-enoate, and sodium hydride is 1:(1 - 1.3):(1.1 - 1.4); toluene or tetrahydrofuran is used as the solvent.

3. The preparation method of deoxyshikonin according to claim 1, characterized in that, In Step 2, the reaction temperature is 65 - 75°C; the basic environment is obtained by potassium carbonate or lithium hydroxide; when the basic environment is obtained by potassium carbonate, the molar ratio of Compound 2 to potassium carbonate is 1:(8 - 10); when the basic environment is obtained by lithium hydroxide, the molar ratio of Compound 2 to lithium hydroxide is 1:(8 - 10); methanol or ethanol is used as the solvent.

4. The preparation method of deoxyshikonin according to claim 1, wherein, In Step 3, when Compound 3 reacts with trifluoroacetic anhydride, the reaction temperature is 0°C, and the molar ratio of Compound 3 to trifluoroacetic anhydride is 1:(2 - 4); when Compound 3 reacts with boron trifluoride dimethyl ether, the reaction temperature is 125 - 130°C, and the molar ratio of Compound 3 to boron trifluoride dimethyl ether is 1:(9 - 11); when Compound 3 reacts with pyrophosphoryl chloride, the reaction temperature is room temperature, and the molar ratio of Compound 3 to pyrophosphoryl chloride is 1:(9 - 11).

5. The preparation method of deoxyshikonin according to claim 1, characterized in that, In Step 4, the oxidizing agent is (diacetoxyiodo)benzene, tert-butyl hydroperoxide, or ammonium cerium(IV) nitrate; among them, when the oxidizing agent is (diacetoxyiodo)benzene, the molar ratio of Compound 4 to (diacetoxyiodo)benzene is 1:(1.5 - 3); when the oxidizing agent is tert-butyl hydroperoxide, the molar ratio of Compound 4 to tert-butyl hydroperoxide is 1:(8 - 10); when the oxidizing agent is ammonium cerium(IV) nitrate, the molar ratio of Compound 4 to ammonium cerium(IV) nitrate is 1:(3 - 5); the reaction solvent is one of acetonitrile, acetone, or tetrahydrofuran; the reaction temperature is room temperature.

6. The preparation method of deoxyshikonin according to claim 1, characterized in that, In Step 5, dichloromethane is used as the solvent, the reaction temperature is 0°C, and the molar ratio of Compound 5 to boron tribromide is 1:(3 - 5).

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