CN116514896A - Synthesis method of dihydrotanshinone I - Google Patents

Synthesis method of dihydrotanshinone I Download PDF

Info

Publication number
CN116514896A
CN116514896A CN202310328640.4A CN202310328640A CN116514896A CN 116514896 A CN116514896 A CN 116514896A CN 202310328640 A CN202310328640 A CN 202310328640A CN 116514896 A CN116514896 A CN 116514896A
Authority
CN
China
Prior art keywords
compound
solvent
reaction
ethyl acetate
crude product
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310328640.4A
Other languages
Chinese (zh)
Inventor
崔孙良
顾震飞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang University ZJU
Original Assignee
Zhejiang University ZJU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang University ZJU filed Critical Zhejiang University ZJU
Priority to CN202310328640.4A priority Critical patent/CN116514896A/en
Publication of CN116514896A publication Critical patent/CN116514896A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a synthesis method of dihydrotanshinone I, which comprises the steps of protecting two ketocarbonyl groups of tanshinone I by benzyl, oxidizing a No. 12 methyl into carboxyl by two steps, and esterifying to obtain a compound 5; then reducing the double bonds at the 1 and 2 positions and hydrolyzing the ester to obtain a racemate 7, and carrying out chiral resolution to obtain a compound 8; the compound 8 is subjected to reduction, sulfonic acid esterification, desulfonation ester and debenzylation protection to obtain the dihydrotanshinone I. The invention starts from the tanshinone I crude product, adopts cheap and easily available raw materials, and synthesizes the high-purity dihydrotanshinone I through multiple steps of reactions which are simple and easy to operate.

Description

Synthesis method of dihydrotanshinone I
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a method for synthesizing dihydrotanshinone I.
Background
Dihydrotanshinone I (DHT) is a fat-soluble phenanthrenequinone compound extracted from root of Salvia Miltiorrhiza bge of Labiatae. Because the DHT contains a unique phenanthrenequinone structure, the DHT and the metabolic products thereof in the body can participate in the oxidation-reduction circulation in the body, so that the DHT has rich pharmacological activities such as antibiosis, anti-inflammation, anti-tumor, cardiovascular protection and the like. In terms of antibiosis, DHT has good antibiosis effect on drug-resistant staphylococcus aureus, bacillus subtilis and other gram-positive bacteria, and can effectively inhibit the growth of tubercle bacillus, in particular has very outstanding helicobacter pylori resistance (MIC) 50/90 0.25/0.5. Mu.g/ml). In anti-inflammatory aspect, in vitro experiments show that DHT can significantly reduce Lipopolysaccharide (LPS) -stimulated THP-T in RAW264.7 cellsRelease of the inflammatory cytokines TNF- α, IL-6 and IL-1β; in an in vivo mouse model, the DHT can obviously improve acute kidney injury caused by LPS and inhibit ear edema of mice caused by dimethylbenzene. In terms of anti-tumor, DHT has good anticancer effect on various solid tumors such as thyroid cancer, esophageal squamous cell carcinoma, liver cancer, breast cancer and the like. In the aspect of cardiovascular protection, DHT can exert myocardial ischemia pre-adaptation effect by inducing transient Reactive Oxygen Species (ROS) production, glutathionylation modification of pyruvate kinase M2 (PKM 2) and nuclear translocation, thereby having remarkable myocardial protection effect.
However, the content of DHT in the root of red-rooted salvia is very low, a large amount of high-purity DHT is difficult to obtain only by the traditional extraction method, and an efficient synthesis method of DHT is not available at present, so that the chiral problem of DHT is difficult to solve. For this purpose, the present invention is proposed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a method for synthesizing dihydrotanshinone I. The method has the advantages of simple and safe raw materials and low cost; the operation is simple, and the practicability is strong.
Description of the terminology:
in the present specification, the compound numbers and the structural formula numbers are completely consistent, and have the same reference relationship, and the structural formula of the compound is taken as a basis.
Room temperature is defined as 25±5 ℃ with the meaning known in the art.
The synthetic route of the method of the invention is as follows:
the technical scheme of the invention is as follows:
a method for synthesizing dihydrotanshinone I comprises the following steps:
(a) In a solvent A, under the action of a palladium catalyst and hydrogen, reducing the ketocarbonyl of a compound 1 (tanshinone I) into phenol, and then under the action of alkali, carrying out nucleophilic reaction with benzyl halide to obtain a compound 2;
(b) Oxidizing compound 2 to compound 3 in solvent B under the action of an oxidizing agent;
(c) Oxidizing the compound 3 into a compound 4 in a mixed solvent C under the action of an oxidant and acid;
(d) In a solvent D, under the action of alkali, performing nucleophilic reaction on the compound 4 and a methylation reagent to obtain a compound 5;
(e) Reducing the compound 5 into a compound 6 in a mixed solvent E under the action of magnesium chips or magnesium powder, ammonium chloride and methanol;
(f) Hydrolyzing the compound 6 into a compound 7 in a mixed solvent F under the action of alkali;
(g) Salifying a compound 7 and chiral amine in a solvent G, heating and dissolving the obtained salt in the solvent G', standing and precipitating the salt at a certain temperature, recrystallizing for a plurality of times, and acidifying the obtained salt to obtain a compound 8;
(h) Reducing compound 8 to compound 9 in solvent H under the action of a reducing agent;
(i) In a solvent I, under the action of alkali and 4-dimethylaminopyridine, reacting the compound 9 with p-toluenesulfonyl chloride to obtain a compound 10;
(j) Removing the p-toluenesulfonate group of the compound 10 in a solvent J under the action of a reducing agent to obtain a compound 11;
(k) In a solvent K, under the action of a palladium catalyst and hydrogen, removing benzyl from the compound 11 to obtain the dihydrotanshinone I.
According to a preferred embodiment of the present invention, the solvent a in step (a) is one of N, N-dimethylformamide, N-dimethylacetamide or tetrahydrofuran; the ratio of the volume of the solvent A to the mole number of the compound 1 is 1-5 mL/1 mmol.
Preferably, according to the present invention, the palladium catalyst in step (a) is palladium on carbon or palladium on carbon hydroxide; the mass ratio of the palladium catalyst to the compound 1 is 2-10:100.
Preferably according to the invention, the base in step (a) is one of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine or N-methylmorpholine; the molar ratio of the alkali to the compound 1 is 2-5:1.
According to a preferred embodiment of the present invention, the benzyl halide in step (a) is benzyl chloride or benzyl bromide, more preferably benzyl chloride; the molar ratio of the halogenated benzyl to the compound 1 is 2.0-5.0:1, and more preferably 2.5:1.
According to a preferred embodiment of the present invention, the reaction temperature for reducing the ketocarbonyl group of compound 1 to phenol in step (a) is 25 to 45 ℃; the reaction time for reducing the ketocarbonyl group of the compound 1 into phenol is 2 to 8 hours.
According to a preferred embodiment of the present invention, the reaction temperature for nucleophilic reaction with benzyl halide in step (a) is 25 to 90 ℃, more preferably 75 ℃; the reaction time for nucleophilic reaction with benzyl halide is 3 to 10 hours, more preferably 5 to 6 hours.
According to a preferred embodiment of the present invention, the step of protecting compound 1 with benzyl group in step (a) to prepare compound 2 comprises: dissolving a compound 1 and a palladium catalyst in a solvent A, replacing hydrogen for a plurality of times, and reacting at 25-45 ℃ in a hydrogen atmosphere; after the reaction liquid is changed from red to colorless and clear, adding the reaction liquid into a system containing alkali, adding benzyl halide, and reacting at 25-90 ℃ under argon atmosphere.
According to a preferred embodiment of the present invention, the post-treatment of the reaction mixture obtained in step (a) for protecting compound 1 with benzyl group to prepare compound 2 is as follows: after the reaction is completed, filtering the obtained reaction solution by using diatomite to remove solids, leaching filter residues by using ethyl acetate, adding water and ethyl acetate into the filtrate, separating the solution, and extracting a water layer by using ethyl acetate; combining the organic layers, washing the organic layers with water for several times, washing the organic layers with saturated salt water for one time, drying the organic layers with anhydrous sodium sulfate, and removing ethyl acetate by rotary evaporation to obtain a crude product; adding a proper amount of petroleum ether and a small amount of ethyl acetate into the crude product, stirring for 10-15 minutes, and filtering to obtain the compound 2.
According to the invention, the solvent B in the step (B) is preferably one of dichloromethane, tetrahydrofuran or dioxane, and more preferably dioxane; the ratio of the volume of the solvent B to the mole number of the compound 2 is 1-5 mL/1 mmol.
According to a preferred embodiment of the present invention, the oxidizing agent in step (b) is selenium dioxide; the molar ratio of the oxidant to the compound 2 is 2-10:1.
According to the present invention, the reaction temperature for oxidizing compound 2 to compound 3 in step (b) is preferably 80 to 120 ℃, more preferably 100 to 110 ℃; the reaction time for oxidizing compound 2 to compound 3 is 18 to 36 hours, more preferably 24 to 30 hours.
According to a preferred embodiment of the present invention, the step of oxidizing compound 2 to compound 3 in step (b) comprises: the compound 2 and the oxidant are dissolved in the solvent B and react at 80-120 ℃.
According to a preferred embodiment of the present invention, the method for working up the reaction mixture obtained by oxidizing compound 2 to compound 3 in step (b) is as follows: after the reaction is completed, adding water and dichloromethane, separating liquid, and extracting a water layer by using dichloromethane; combining the organic layers, washing the organic layers with water for several times, washing the organic layers with saturated salt water for one time, drying the organic layers with anhydrous sodium sulfate, and removing dichloromethane by rotary evaporation to obtain a crude product; adding a proper amount of petroleum ether and a small amount of ethyl acetate into the crude product, stirring for 10-15 minutes, and filtering to obtain the compound 3.
According to the invention, the mixed solvent C in the step (C) is a mixed solvent of tetrahydrofuran, water and tertiary butanol, and the volume ratio is 1-10:1-3:1, preferably 6-9:3:1; the ratio of the volume of the mixed solvent C to the mole number of the compound 3 is 10-20 mL/1 mmol.
Preferably according to the invention, the oxidising agent in step (c) is sodium chlorite; the molar ratio of the oxidant to the compound 3 is 1.5-5.0:1, preferably 3.0:1.
Preferably according to the invention, the acid in step (c) is sulfamic acid, resorcinol, sodium dihydrogen phosphate or potassium dihydrogen phosphate, preferably sulfamic acid; the molar ratio of the acid to the compound 3 is 1.5-5.0:1, preferably 3.0:1.
According to a preferred embodiment of the present invention, the reaction temperature for oxidizing compound 3 to compound 4 in step (c) is-20 to 0 ℃, more preferably-10 to-5 ℃; the reaction time for oxidizing compound 3 to compound 4 is 10 to 30 minutes, more preferably 15 to 20 minutes;
according to a preferred embodiment of the present invention, the step of oxidizing compound 3 to compound 4 in step (c) comprises: dissolving the compound 3 and acid in a mixed solvent C, and stirring for 10-20 minutes at the temperature of-20-0 ℃; then slowly dripping the aqueous solution of the oxidant, and reacting at the temperature of-20 to 0 ℃ after the dripping is finished.
According to a preferred embodiment of the present invention, the method for working up the reaction mixture obtained by oxidizing compound 3 to compound 4 in step (c) is as follows: after the reaction is completed, dropwise adding sodium sulfite aqueous solution to quench redundant oxidant at-20-0 ℃; after the dripping is finished, ethyl acetate is added, and after liquid separation, the water layer is extracted by ethyl acetate; the organic layers were combined, washed with water several times, once with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to remove ethyl acetate to give crude product. Adding a proper amount of petroleum ether and a small amount of ethyl acetate into the crude product, stirring for 10-15 minutes, and filtering to obtain the compound 4.
According to a preferred embodiment of the present invention, the solvent D in step (D) is one of dichloromethane, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide or N, N-dimethylacetamide; the ratio of the volume of the solvent D to the number of moles of the compound 4 is 1 to 5 mL/1 mmol.
Preferably according to the invention, the base in step (d) is one of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine or N-methylmorpholine; the molar ratio of the alkali to the compound 4 is 1.5-5.0:1.
Preferably according to the invention, the methylating agent in step (d) is potassium iodide or dimethyl sulphate; the molar ratio of the methylating agent to the compound 4 is 2-10:1, preferably 4-6:1.
According to the present invention, the reaction temperature for converting the methyl group of the compound 4 into the compound 5 in the step (d) is preferably 25 to 60 ℃, more preferably 45 to 55 ℃; the reaction time for methylation of compound 4 to compound 5 is 1.5 to 8.0 hours, more preferably 3.0 to 5.0 hours.
According to a preferred embodiment of the present invention, the step of methylating compound 4 to compound 5 in step (d) comprises: dissolving the compound 4 and alkali in a solvent D, and stirring for 10-20 minutes at 25 ℃; then adding methylating reagent dropwise, and reacting at 25-60 ℃.
According to a preferred embodiment of the present invention, the reaction mixture obtained by methylation of compound 4 to compound 5 in step (d) is worked up as follows: after the reaction is completed, filtering to remove solids, leaching filter residues with ethyl acetate, and collecting filtrate to spin dry to obtain a crude product; adding a proper amount of petroleum ether and a small amount of ethyl acetate into the crude product, stirring for 10-15 minutes, and filtering to obtain the compound 5.
According to the invention, the mixed solvent E in the step (E) is a mixed solvent of anhydrous tetrahydrofuran and anhydrous methanol, and the volume ratio is 1-5:1, and is more preferably 4:1; the ratio of the volume of the mixed solvent E to the mole number of the compound 5 is 15-30 mL/1 mmol.
According to the invention, the molar ratio of magnesium turnings or powder to compound 5 in step (e) is preferably 10 to 30:1, preferably 20:1.
According to a preferred embodiment of the invention, the molar ratio of ammonium chloride to compound 5 in step (e) is 3 to 8:1, preferably 5 to 6:1.
According to a preferred embodiment of the present invention, the reaction temperature for reducing compound 5 to compound 6 in step (e) is 0 to 45 ℃, more preferably 25 to 30 ℃; the reaction time for reducing compound 5 to compound 6 is 1 to 5 hours, more preferably 2 to 3 hours.
According to a preferred embodiment of the present invention, the step of reducing compound 5 to compound 6 in step (e) comprises: dissolving the compound 5, magnesium chips or magnesium powder and ammonium chloride in a mixed solvent E, and carrying out vigorous stirring reaction at 0-45 ℃ under the argon atmosphere.
According to a preferred embodiment of the present invention, the reaction mixture obtained by reducing compound 5 to compound 6 in step (e) is worked up as follows: after the reaction is completed, adding an ammonium chloride aqueous solution at 0 ℃ until the solution is clear; adding ethyl acetate, separating, extracting the water layer with ethyl acetate, mixing the organic layers, washing with water for several times, washing with saturated salt water once, drying the organic layer with anhydrous sodium sulfate, and removing solvent by rotary evaporation to obtain crude product; adding a proper amount of petroleum ether and a small amount of ethyl acetate into the crude product, stirring for 10-15 minutes, and filtering to obtain the compound 6.
According to the invention, the mixed solvent F in the step (F) is a mixed solvent of tetrahydrofuran, methanol and water, and the volume ratio is 5-3:3-1:1; the ratio of the volume of the mixed solvent F to the mole number of the compound 6 is 3-10 mL/1 mmol.
Preferably according to the present invention, the base in step (f) is one of lithium hydroxide, sodium hydroxide or potassium hydroxide; the molar ratio of the alkali to the compound 6 is 1.5-5.0:1, preferably 2.0-3.0:1.
According to the present invention, the reaction temperature for hydrolyzing the compound 6 to the compound 7 in the step (f) is preferably 25 to 60 ℃, more preferably 40 to 50 ℃; the reaction time for hydrolyzing the compound 6 to the compound 7 is 1 to 5 hours, more preferably 2 to 3 hours.
According to a preferred embodiment of the present invention, the step of hydrolyzing compound 6 to compound 7 in step (f) comprises: dissolving the compound 6 in the mixed solvent E, dropwise adding an aqueous solution of alkali, and reacting at 25-60 ℃.
According to a preferred embodiment of the present invention, the post-treatment of the reaction mixture obtained by hydrolyzing compound 6 to compound 7 in step (f) is as follows: after the reaction is completed, removing the organic solvent by rotary evaporation; acidifying the concentrated solution with hydrochloric acid, adding dichloromethane, separating, extracting the water layer with dichloromethane, mixing the organic layers, washing with saturated saline water once, drying the organic layers with anhydrous sodium sulfate, and removing dichloromethane by rotary evaporation to obtain crude product; adding a proper amount of petroleum ether and a small amount of ethyl acetate into the crude product, stirring for 10-15 minutes, and filtering to obtain the compound 7.
According to a preferred embodiment of the present invention, the solvent G in step (G) is one of dichloromethane, ethyl acetate, tetrahydrofuran, dioxane, methanol, ethanol or isopropanol; the ratio of the volume of the solvent G to the mole number of the compound 7 is 10-40 mL/1 mmol.
According to the invention, the solvent G' used for the recrystallization in the step (G) is one or more of dichloromethane, ethyl acetate, tetrahydrofuran, methanol, ethanol and isopropanol, and more preferably is a single solvent isopropanol or a mixed solvent of isopropanol and methanol in a volume ratio of 50-200:1; the ratio of the number of moles of the solvent G' to the number of moles of the compound 7 used for the recrystallization is 25 to 60 mL/1 mmol.
According to a preferred aspect of the present invention, the chiral amine in step (g) is one of (R) - (+) -alpha-methylbenzylamine, (S) - (-) -alpha-methylbenzylamine, (R) - (+) -N-benzyl-1-phenylethylamine, (S) - (-) -N-benzyl-1-phenylethylamine, (R) - (-) -2-amino-1-butanol, (S) - (+) -2-amino-1-butanol, (R) - (-) -2-amino-3-methyl-1-butanol, (S) - (+) -2-amino-3-methyl-1-butanol, (R) - (-) -2-amino-4-methyl-1-pentanol or (S) - (+) -2-amino-4-methyl-1-pentanol, more preferably (R) - (+) -alpha-methylbenzylamine; the molar ratio of the chiral amine to the compound 7 is 1.05-1.50:1.
According to a preferred embodiment of the present invention, the reaction temperature of salifying compound 7 with chiral amine in step (g) is from 25 to 50 ℃, more preferably from 25 to 30 ℃; the reaction time for salifying the compound 7 with the chiral amine is 10 to 30 minutes, and more preferably 15 to 25 minutes.
According to the present invention, the temperature at which the obtained salt is heated to be dissolved in step (g) is preferably 80 to 130 ℃, more preferably 100 to 115 ℃.
According to the present invention, the temperature at which the obtained salt is allowed to stand and precipitate in the step (g) is preferably 25 to 65 ℃, more preferably 30 to 50 ℃; the time for allowing the obtained salt to stand and precipitate is 1.0 to 6.0 hours, more preferably 1.5 to 4.0 hours.
According to the invention, the number of recrystallisation steps (g) is preferably 1 to 4, preferably 2.
According to a preferred embodiment of the present invention, the step of salifying compound 7 with chiral amine in step (g) comprises: dissolving the compound 7 in a solvent G, adding chiral amine, reacting at 25-50 ℃, and removing the solvent by rotary evaporation after full salification to obtain the salt of the compound 7.
According to a preferred embodiment of the present invention, the step (g) of recrystallizing and acidifying the salt of compound 7 with a chiral amine to obtain compound 8 comprises: heating and dissolving a salt formed by the compound 7 and chiral amine in a solvent G'; after complete dissolution, keeping the solution at 25-65 ℃ for standing precipitation, and filtering to obtain salt; recrystallizing for 1-4 times according to the method, adding ethyl acetate into salt obtained by recrystallization, acidifying with hydrochloric acid, and extracting a water layer with ethyl acetate; the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and then rotary evaporated to remove ethyl acetate to give compound 8.
According to a preferred embodiment of the present invention, the solvent H in step (H) is one of anhydrous tetrahydrofuran, anhydrous dioxane or anhydrous ethanol; the ratio of the volume of the solvent H to the mole number of the compound 8 is 3-10 mL/1 mmol.
According to a preferred embodiment of the present invention, the reducing agent in step (h) is one of lithium aluminum hydride, sodium borohydride or borane tetrahydrofuran complex, more preferably lithium aluminum hydride; the mol ratio of the reducing agent to the compound 8 is 1.5-3.5:1.
According to a preferred embodiment of the present invention, the reaction temperature for reducing compound 8 to compound 9 in step (h) is-20 to 25 ℃, more preferably-10 to-5 ℃; the reaction time for reducing the compound 8 to the compound 9 is 0.5 to 2 hours.
According to a preferred embodiment of the present invention, the step of reducing compound 8 to compound 9 in step (h) comprises: and (3) dissolving the compound 8 in a mixed solvent H, adding a reducing agent, and reacting at-20-25 ℃ in an argon atmosphere.
According to a preferred embodiment of the present invention, the reaction mixture obtained by reducing compound 8 to compound 9 in step (h) is worked up as follows: after the reaction is completed, adding saturated ammonium chloride aqueous solution or dilute hydrochloric acid to quench the reaction, adding ethyl acetate, separating the liquid, and extracting the water layer with ethyl acetate; combining the organic layers, washing the organic layers once with saturated saline, drying the organic layers with anhydrous sodium sulfate, and removing ethyl acetate by rotary evaporation to obtain a crude product; purifying the crude product by silica gel column chromatography to obtain a compound 9; the silica gel for silica gel column chromatography is 200-300 meshes of silica gel, and the eluent is petroleum ether with the volume ratio: dichloromethane: ethyl acetate=10:2:1 mixed solvent.
According to a preferred embodiment of the present invention, the solvent I in step (I) is anhydrous dichloromethane or anhydrous tetrahydrofuran; the ratio of the volume of the solvent I to the mole number of the compound 9 is 3-15 mL/1 mmol.
Preferably according to the invention, the base in step (i) is one of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine or N-methylmorpholine; the molar ratio of the alkali to the compound 9 is 2-5:1.
According to the invention, the molar ratio of 4-dimethylaminopyridine to compound 9 in step (i) is preferably from 0.1 to 1:1, more preferably from 0.4 to 0.6.
According to the invention, the molar ratio of p-toluenesulfonyl chloride to compound 9 in step (i) is preferably 2 to 10:1, more preferably 5 to 8:1.
According to a preferred embodiment of the present invention, the reaction temperature for the sulphonic acid esterification of compound 9 to compound 10 in step (i) is between 25 and 50 ℃, more preferably between 35 and 45 ℃; the reaction time for the sulfonation of the compound 9 to the compound 10 is 1 to 5 hours, more preferably 2 to 3 hours.
According to a preferred embodiment of the present invention, the step of sulphonic acid esterification of compound 9 to compound 10 in step (i) comprises: compound 9, p-toluenesulfonyl chloride and 4-dimethylaminopyridine were dissolved in solvent H and reacted at 25-50 ℃ under argon atmosphere.
According to a preferred embodiment of the present invention, the post-treatment of the reaction mixture obtained by the sulfonation of compound 9 to compound 10 in step (i) is as follows: after the reaction is completed, adding water, separating liquid, and extracting a water layer by using dichloromethane; the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and the dichloromethane was removed by rotary evaporation to give the crude product. Purifying the crude product by silica gel column chromatography to obtain a compound 10; the silica gel for silica gel column chromatography is 200-300 meshes of silica gel, and the eluent is petroleum ether with the volume ratio: dichloromethane: ethyl acetate=20:2:1 mixed solvent.
According to a preferred embodiment of the present invention, the solvent J in step (J) is anhydrous dichloromethane, anhydrous tetrahydrofuran or anhydrous dioxane, more preferably anhydrous tetrahydrofuran; the ratio of the volume of the solvent J to the mole number of the compound 10 is 3-15 mL/1 mmol.
According to a preferred embodiment of the present invention, the reducing agent in step (j) is one of lithium aluminum hydride, sodium borohydride, lithium borohydride or triethylsilane, and more preferably lithium aluminum hydride; the molar ratio of the reducing agent to the compound 10 is 2-10:1, preferably 4-5:1.
According to the present invention, the reaction temperature for reducing compound 10 to compound 11 in step (j) is preferably 0 to 60 ℃, more preferably 35 to 45 ℃; the reaction time for reducing compound 10 to compound 11 is 0.5 to 5 hours, more preferably 1 to 2 hours.
According to a preferred embodiment of the present invention, the step of sulphonic acid esterification of compound 9 to compound 10 in step (j) comprises: compound 9, p-toluenesulfonyl chloride and 4-dimethylaminopyridine were dissolved in solvent H and reacted at 25-50 ℃ under argon atmosphere.
According to a preferred embodiment of the present invention, the method for working up the reaction mixture obtained by reducing compound 10 to compound 11 in step (j) is as follows: after the reaction is completed, adding saturated ammonium chloride aqueous solution or dilute hydrochloric acid to quench the rest reducing agent, adding ethyl acetate, separating liquid, and extracting a water layer by using ethyl acetate; combining the organic layers, washing the organic layers once with saturated saline, drying the organic layers with anhydrous sodium sulfate, and removing ethyl acetate by rotary evaporation to obtain a crude product; purifying the crude product by silica gel column chromatography to obtain a compound 11; the silica gel for silica gel column chromatography is 200-300 meshes of silica gel, and the eluent is petroleum ether with the volume ratio: dichloromethane: ethyl acetate=20:2:1 mixed solvent.
According to the invention, the solvent K in the step (K) is one or more of tetrahydrofuran, ethyl acetate or methanol, and is more preferably a mixed solvent of ethyl acetate and methanol in a volume ratio of 3:1; the ratio of the volume of the solvent K to the mole number of the compound 11 is 3-15 mL/1 mmol.
Preferably according to the present invention, the palladium catalyst in step (k) is palladium on carbon or palladium on carbon hydroxide; the mass ratio of the palladium catalyst to the compound 11 is 2-10:100, preferably 5:100.
according to a preferred embodiment of the present invention, the reaction temperature in step (k) for debenzylating compound 11 to a compound of formula (I) is from 25 to 50℃and more preferably from 35 to 45 ℃; the reaction time for debenzylating the compound 11 to the compound of formula (I) is 0.5 to 5 hours, more preferably 1 to 2 hours.
According to a preferred embodiment of the present invention, the step of debenzylating compound 11 in step (k) to a compound of formula (I) comprises: compound 11 and palladium catalyst are dissolved in solvent K, and after hydrogen is replaced for a plurality of times, the mixture is reacted under the hydrogen atmosphere at 25-50 ℃.
According to a preferred embodiment of the present invention, the post-treatment of the reaction mixture obtained in step (k) by debenzylating the compound 11 to the compound of formula (I) is carried out as follows: after the reaction is completed, the diatomite is filtered to remove the palladium catalyst, filter residues are leached by ethyl acetate, filtrate is collected, and the ethyl acetate is removed by rotary evaporation to obtain a crude product; purifying the crude product by silica gel column chromatography to obtain a compound of formula (I), namely dihydrotanshinone I; the silica gel for silica gel column chromatography is 200-300 meshes of silica gel, and the eluent is methylene dichloride with the volume ratio: methanol=50:1 mixed solvent.
The invention has the technical characteristics and beneficial effects that:
1. the invention starts from sallow purity tanshinone I or tanshinone I totally synthesized according to the report of related literature, and oxidizes the 12-methyl into acid and esterifies after protecting the ketocarbonyl of tanshinone I by benzyl; reducing double bonds at 1 and 2 positions, hydrolyzing ester into acid, and then resolving by using chiral amine to obtain a chiral acid compound 8 with high purity; finally, the carboxyl of the compound 8 is converted into methyl, and debenzylation is carried out to obtain the high-purity dihydrotanshinone I.
2. The invention uses benzyl to protect two ketocarbonyl groups of tanshinone I, which greatly improves the yield of each step of reaction.
3. According to the invention, after the 12-methyl of tanshinone I is oxidized into carboxylic acid, the 1-and 2-double bonds can be reduced efficiently after esterification, and the acid and chiral amine can be used for salifying to perform efficient chiral resolution.
4. Intermediates involved in the synthetic route of the present invention: the compound 8, the compound 9 and the compound 10 can be quickly and efficiently converted into other dihydrotanshinone I derivatives, which provides great convenience for the preparation of the dihydrotanshinone I and the derivatives thereof.
Drawings
FIG. 1 is an HPLC chromatogram of compound 7 obtained by the method of the present invention;
FIG. 2 is an HPLC chromatogram of compound 8 obtained by the method of the present invention;
FIG. 3 shows the X-ray crystals of compound 10 obtained by the method of the present invention.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention, but is not intended to limit the invention thereto.
Example 1:
commercially available tanshinone I (30.0 g,102 mmol) and 10% palladium on carbon (600 mg,2 wt%) were weighed into a 250mL two-necked flask equipped with a magnetic stirrer, 150mL of N, N-dimethylformamide was added thereto, and the mixture was reacted at room temperature for 3 to 5 hours after hydrogen substitution several times. After the reaction solution was changed from red to colorless and clear, it was transferred by syringe to a 250mL two-necked flask equipped with potassium carbonate (56.3 g,408 mmol) and a magnetic stirrer under argon protection, stirred at room temperature for 10 minutes, benzyl chloride (21.9 mL,255 mmol) was added, and the temperature was raised to 75℃for reaction for 5 to 6 hours. After the reaction was completed, the solid was removed by filtration through celite, the residue was rinsed with ethyl acetate, 125mL of water and 50mL of ethyl acetate were added to the filtrate, and after separation, the aqueous layer was extracted with ethyl acetate (50 ml×3). The organic layers were combined, washed with water several times, once with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to remove ethyl acetate to give crude product. After adding a proper amount of petroleum ether and a small amount of ethyl acetate to the crude product and stirring for 10-15 minutes, the mixture was filtered to obtain a white or pale yellow solid (32.7 g,71.3mmol, 69.9%). 1 H NMR(500MHz,CDCl 3 )δ9.78(d,J＝8.0Hz,1H),8.30(d,J＝9.0Hz,1H),8.06(d,J＝9.0Hz,1H),7.58(d,J＝6.0Hz,2H),7.54–7.29(m,11H),5.43(s,2H),5.06(s,2H),2.82(s,3H),2.37(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ149.3,145.9,145.9,141.6,137.6,137.4,134.5,131.3,130.3,128.9,128.6,128.5,128.5,128.1,128.1,127.5,126.3,125.9,122.8,122.3,120.5,118.9,117.2,116.4,76.8,75.5,20.7,9.7.
Example 2:
compound 2 (5.0 g,10.9 mmol) and selenium dioxide (2.4 g,21.8 mmol) were weighed into a 100mL single-necked flask equipped with a magnetic stirrer, 30mL of dioxane was added, and the reaction was refluxed for 24-30 hours. After the reaction was completed, 50mL of water and 30mL of methylene chloride were added, and after separation, the aqueous layer was extracted with methylene chloride (15 mL. Times.3). The organic layers were combined, washed with water several times, once with saturated brine, dried over anhydrous sodium sulfate, and the dichloromethane was removed by rotary evaporation to give the crude product. After adding a proper amount of petroleum ether and a small amount of ethyl acetate to the crude product and stirring for 10-15 minutes, a white solid (3.8 g,8.1mmol, 74.3%) was obtained by filtration. 1 H NMR(500MHz,CDCl 3 )δ10.32(s,1H),9.78(d,J＝9.0Hz,1H),8.38(s,1H),8.27(d,J＝9.0Hz,1H),8.12(d,J＝9.0Hz,1H),7.60–7.57(m,2H),7.56–7.50(m,2H),7.46–7.38(m,5H),7.35–7.30(m,3H),5.47(s,2H),5.09(s,2H),2.82(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ186.11,150.31,149.53,147.67,144.85,136.94,136.85,134.74,131.55,129.93,128.87,128.62,128.48,128.32,128.13,126.69,125.92,123.74,123.73,123.49,118.20,117.17,116.77,76.77,75.64,20.60.
Example 3:
compound 3 (5.0 g,10.6 mmol) and sulfamic acid (3.1 g,31.8 mmol) were weighed into a 250mL single-necked flask equipped with a magnetic stirrer and 90mL of tetrahydrofuran and 10mL of t-butanol were added. After stirring at-10℃for 20 minutes, 30mL of an aqueous solution of sodium chlorite (2.9 g,31.8 mmol) was added dropwise. After the dripping is finished, the reaction is carried out for 20 to 30 minutes at the temperature of minus 10 ℃. After the reaction is completed, adding thionine dropwiseSodium acid (4.0 g,31.8 mmol) in water. After completion of the dropwise addition, 50mL of ethyl acetate was added, and after separation, the aqueous layer was extracted with ethyl acetate (15 mL. Times.3). The organic layers were combined, washed with water several times, once with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to remove ethyl acetate to give crude product. After adding a proper amount of petroleum ether and a small amount of ethyl acetate to the crude product and stirring for 10-15 minutes, a white solid (4.8 g,9.8mmol, 92.6%) was obtained by filtration. 1 H NMR(500MHz,DMSO)δ13.01(s,1H),9.58(d,J＝8.5Hz,1H),8.82(s,1H),8.22(d,J＝9.0Hz,1H),8.11(d,J＝9.0Hz,1H),7.59–7.54(m,2H),7.52–7.50(m,1H),7.48–7.40(m,3H),7.38–7.33(m,6H),5.25(s,2H),4.93(s,2H),2.74(s,3H)； 13 C NMR(126MHz,DMSO)δ163.70,152.79,149.30,147.94,145.12,137.95,137.21,135.09,131.40,129.61,128.93,128.82,128.78,128.55,128.48,128.44,128.19,127.01,125.57,124.19,122.48,118.47,117.32,116.72,116.38,76.52,75.25,20.53.
Example 4:
compound 4 (20.0 g,40.9 mmol) and potassium carbonate (16.9 g,122.7 mmol) were weighed into a 250mL single-necked flask equipped with a magnetic stirrer, 100mL of acetone was added thereto, and after stirring at room temperature for 10 minutes, methyl iodide (15.3 mL,245.4 mmol) was added dropwise thereto and the temperature was raised to 45℃for reaction for 3 to 5 hours. After the reaction is completed, filtering to remove solids, leaching filter residues with ethyl acetate, collecting filtrate, and removing solvent by rotary evaporation to obtain a crude product. After adding a proper amount of petroleum ether and a small amount of ethyl acetate to the crude product and stirring for 10-15 minutes, the mixture was filtered to obtain a white or pale yellow solid (19.7 g,39.1mmol, 95.6%). 1 H NMR(500MHz,CDCl 3 )δ9.77–9.72(m,1H),8.38(s,1H),8.27(d,J＝9.0Hz,1H),8.08(d,J＝9.0Hz,1H),7.61–7.55(m,2H),7.52–7.45(m,4H),7.39–7.28(m,6H),5.40(s,2H),5.06(s,2H),3.80(s,3H),2.80(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ163.02,151.38,149.72,148.33,145.11,137.71,137.17,134.59,131.49,129.87,128.94,128.67,128.45,128.27,128.09,128.02,127.83,126.57,126.07,123.55,123.23,118.33,117.07,116.83,115.57,76.89,75.51,51.96,20.58.
Example 5:
compound 5 (2.5 g,5.0 mmol), magnesium turnings (2.4 g,100 mmol) and ammonium chloride (1.3 g,25 mmol) were weighed into a 250mL two-necked flask equipped with a magnetic stirrer, 100mL of anhydrous tetrahydrofuran and 25mL of anhydrous methanol were added, the argon was replaced several times, and the reaction was vigorously stirred at room temperature for 2-3 hours. After the reaction was completed, an aqueous ammonium chloride solution was added at 0 ℃ until the solution was clear. 50mL of ethyl acetate was added, the mixture was separated, the aqueous layer was extracted with ethyl acetate (15 mL. Times.3), the organic layers were combined, washed with water several times, and once with saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give a crude product. After adding a proper amount of petroleum ether and a small amount of ethyl acetate to the crude product and stirring for 10-15 minutes, a white solid (2.3 g,4.6mmol, 92.0%) was obtained by filtration. 1 H NMR(500MHz,CDCl 3 )δ9.73–9.63(m,1H),7.88(s,2H),7.54–7.50(m,2H),7.48–7.44(m,2H),7.44–7.31(m,8H),5.51(d,J＝11.0Hz,1H),5.18(d,J＝11.0Hz,1H),4.98(d,J＝10.5Hz,1H),4.96–4.85(m,3H),4.44(dd,J＝9.5,6.5Hz,1H),3.66(s,3H),2.76(s,3H)； 13 C NMR(126MHz,CDCl3)δ172.71,153.96,148.03,144.41,137.72,137.21,134.38,131.97,129.88,128.88,128.53,128.40,128.22,128.14,128.00,126.31,126.08,126.05,121.94,119.95,115.61,115.28,75.27,75.02,52.53,47.42,20.58.
Example 6:
compound 6 (10.0 g,19.8 mmol) was weighed into a 250mL single-necked flask equipped with a magnetic stirrer, 75mL of tetrahydrofuran and 25mL of methanol were added, 20mL of 2M aqueous sodium hydroxide solution was added dropwise, and the reaction was carried out at 45℃for 2-3 hours. After the reaction was completed, tetrahydrofuran and methanol were removed by rotary evaporation. Adding 1N hydrochloric acid into the concentrated solution to acidify until the pH value is 1-2, and adding two100mL of methyl chloride was separated, the aqueous layer was extracted with methylene chloride (50 mL. Times.3), the organic layers were combined, washed once with saturated brine, and the organic layers were dried over anhydrous sodium sulfate, and the methylene chloride was removed by rotary evaporation to give a crude product. After adding a proper amount of petroleum ether and a small amount of ethyl acetate to the crude product and stirring for 10-15 minutes, a white solid (9.2 g,18.8mmol, 94.9%) was obtained by filtration. Chiral HPLC patterns are shown in fig. 1, and the chromatographic conditions are as follows: daicel Chiralcel AD-H (0.46 cm. Times.25 cm), hexane:i-PrOH=60:40; v=1.0 mL/min; λ=254 nm. 1 H NMR(400MHz,CDCl 3 )δ9.75–9.70(m,1H),7.95(d,J＝9.2Hz,1H),7.91(d,J＝9.2Hz,1H),7.63–7.57(m,2H),7.56–7.51(m,2H),7.51–7.42(m,3H),7.42–7.33(m,5H),5.51(d,J＝11.2Hz,1H),5.42(d,J＝11.2Hz,1H),5.14–5.09(m,1H),5.04(d,J＝10.4Hz,1H),5.01(d,J＝10.4Hz,1H),4.83–4.76(m,1H),4.14–4.05(m,1H),2.81(s,1H)； 13 C NMR(101MHz,CDCl 3 )δ174.00,153.69,146.45,144.12,137.02,136.52,134.58,132.06,129.83,129.08,129.05,128.87,128.78,128.74,128.65,128.39,128.34,126.52,126.32,125.95,122.44,119.88,116.07,113.68,76.65,75.52,74.09,47.35,20.60.
Example 7:
compound 7 (3.8 g,7.7 mmol) was weighed into a 500mL single-necked flask equipped with a magnetic stirrer, 150mL of methylene chloride was added, and (R) - (+) -alpha-methylbenzylamine (1.21 g,10 mmol) was added thereto, followed by stirring at room temperature for 15-25 minutes. After both had fully salified, the dichloromethane was removed by rotary evaporation to give a yellow solid. 350mL of isopropanol are added, the yellow solid is completely dissolved by refluxing and stirring, and if partial salt is still not dissolved, methanol or isopropanol can be properly added until the solution is completely clarified. After the mixture is completely clarified, keeping the solution at 30-40 ℃ for standing to precipitate solid for 3-4 hours. Filtering, rotary evaporating to remove isopropanol, collecting the filtrate, placing the white filter cake in 250mL single-mouth bottle equipped with magnetic stirrer, adding 200mL isopropanol, refluxing and stirring to dissolve the white solid completely, and adding methanol or isopropanol if partial salt is not dissolved Propanol was allowed to clear the solution completely. After the mixture is completely clarified, keeping the solution at 40-50 ℃ for standing to precipitate solid for 1.5-2 hours. The filtrate was filtered, the isopropanol was removed by rotary evaporation, the white cake was collected and after addition of ethyl acetate, acidified with 1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate (20 mL. Times.3). The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and ethyl acetate was removed by rotary evaporation to give a white solid (1.1 g,2.0mmol, 26.0%). Chiral HPLC patterns are shown in fig. 2, and the chromatographic conditions are as follows: daicel Chiralcel AD-H (0.46 cm. Times.25 cm), hexane:i-PrOH=60:40; v=1.0 mL/min; λ=254 nm. 1 H NMR(400MHz,CDCl 3 )δ9.70–9.67(m,1H),7.92(d,J＝9.2Hz,1H),7.87(d,J＝9.2Hz,1H),7.60–7.53(m,2H),7.53–7.48(m,2H),7.47–7.39(m,3H),7.38–7.29(m,5H),5.46(d,J＝11.2Hz,1H),5.39(dd,J＝11.2,3.2Hz,1H),5.11–5.07(m,1H),5.02–4.94(m,2H),4.75(t,J＝9.6Hz,1H),4.09–3.95(m,1H),2.77(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ173.88,153.67,146.39,144.10,137.00,136.47,134.60,132.06,129.82,129.15,129.12,128.87,128.82,128.77,128.66,128.41,128.36,126.52,126.34,125.94,122.48,119.88,116.10,113.63,76.72,75.53,74.05,47.36,20.61.
Example 8:
compound 8 (2.5 g,5.1 mmol) was weighed into a 100mL two-necked flask equipped with a magnetic stirrer and replaced with argon several times. 50mL of anhydrous tetrahydrofuran was added, and after cooling to-5 ℃, lithium aluminum hydride (3838 mg,10.2 mmol) was added in portions, and the mixture was reacted at-5℃for 30 to 45 minutes. After the reaction was completed, the remaining lithium aluminum hydride was quenched by adding a saturated aqueous ammonium chloride solution, 25mL of ethyl acetate was added, and after separation, the aqueous layer was extracted with ethyl acetate (15 mL. Times.3). The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to remove ethyl acetate to give crude product. The crude product was purified by silica gel column chromatography to give a colorless gum or white foam solid (1.8 g,3.8mmol, 74.3%). 1 H NMR(500MHz,CDCl 3 )δ9.71(dd,J＝8.0,2.0Hz,1H),7.89(s,2H),7.59–7.55(m,2H),7.52–7.39(m,7H),7.38–7.34(m,3H),5.42(d,J＝11.0Hz,1H),5.36(d,J＝11.0Hz,1H),5.06(d,J＝10.5Hz,1H),4.98(d,J＝10.5Hz,1H),4.76(t,J＝9.0Hz,1H),4.51(dd,J＝9.0,6.0Hz,1H),3.89(dd,J＝10.5,7.0Hz,1H),3.79(dd,J＝10.5,5.5Hz,1H),3.72–3.67(m,1H),2.78(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ153.91,147.69,143.86,137.20,136.92,134.44,131.88,129.93,128.94,128.88,128.59,128.56,128.49,128.22,128.09,126.14,125.94,125.68,121.93,119.98,117.69,115.81,76.27,75.31,74.53,65.16,45.42,20.59.
Example 9:
compound 9 (2.5 g,5.2 mmol), p-toluenesulfonyl chloride (5.0 g,26.2 mmol) and 4-dimethylaminopyridine (318 mg,2.6 mmol) were weighed into a 100mL two-necked flask equipped with a magnetic stirrer and replaced with argon several times. 50mL of anhydrous methylene chloride and triethylamine (2.9 mL,20.8 mmol) were added and the mixture was reacted at 40℃for 2 to 3 hours. After completion of the reaction, 30mL of water was added, the mixture was separated, and the aqueous layer was extracted with methylene chloride (15 mL. Times.3). The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and the dichloromethane was removed by rotary evaporation to give the crude product. The crude product was purified by silica gel column chromatography to give a white solid (2.7 g,4.3mmol, 82.7%) whose X-ray crystals are shown in FIG. 3. 1 H NMR(400MHz,CDCl 3 )δ9.73–9.67(m,1H),7.91(d,J＝9.2Hz,1H),7.86(d,J＝9.2Hz,1H),7.77(d,J＝8.0Hz,2H),7.60–7.55(m,2H),7.54–7.49(m,2H),7.49–7.42(m,3H),7.41–7.33(m,5H),7.31(d,J＝8.0Hz,2H),5.36(d,J＝11.2Hz,1H),5.29(d,J＝11.2Hz,1H),5.00(d,J＝10.4Hz,1H),4.93(d,J＝10.4Hz,1H),4.70(t,J＝9.2Hz,1H),4.67–4.60(m,1H),4.56(dd,J＝9.6,3.6Hz,1H),4.12–4.02(m,1H),3.83–3.73(m,1H),2.80(s,3H),2.44(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ153.83,148.02,144.97,144.04,137.28,137.16,134.49,132.85,131.95,129.97,129.85,128.87,128.62,128.61,128.34,128.26,128.22,127.94,126.19,125.99,121.98,119.87,115.61,114.48,75.84,75.23,74.84,70.34,42.25,21.70,20.63.
Example 10:
compound 10 (2.7 g,4.3 mmol) was weighed into a 100mL two-necked flask equipped with a magnetic stirrer and replaced with argon several times. 50mL of anhydrous tetrahydrofuran was added thereto, lithium aluminum hydride (650 mg,17.2 mmol) was added thereto in portions at room temperature, and the mixture was reacted at 45℃for 1 to 2 hours. After the reaction was completed, the remaining lithium aluminum hydride was quenched by adding a saturated aqueous ammonium chloride solution, 25mL of ethyl acetate was added, and after separation, the aqueous layer was extracted with ethyl acetate (15 mL. Times.3). The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to remove ethyl acetate to give crude product. The crude product was purified by column chromatography on silica gel to give a colourless gum (1.9 g,4.1mmol, 95.3%). 1 H NMR(400MHz,CDCl 3 )δ9.78(dd,J＝8.0,2.4Hz,1H),7.98(d,J＝9.2Hz,1H),7.94(d,J＝9.2Hz,1H),7.66–7.62(m,2H),7.57–7.49(m,5H),7.48–7.40(m,5H),5.50(d,J＝11.2Hz,1H),5.36(d,J＝11.2Hz,1H),5.12(d,J＝10.4Hz,1H),5.04(d,J＝10.4Hz,1H),4.87(t,J＝8.8Hz,1H),4.39(dd,J＝8.8,6.0Hz,1H),3.80–3.75(m,1H),2.84(s,3H),1.51(d,J＝7.2Hz,3H)； 13 C NMR(101MHz,CDCl 3 )δ153.10,148.71,144.23,137.87,137.52,134.37,131.82,130.11,128.92,128.59,128.54,128.41,128.15,128.11,127.91,126.04,125.21,121.82,121.62,120.12,115.55,79.34,75.76,75.26,37.04,20.67,19.70.
Example 11:
compound 11 (1.9 g,4.1 mmol) and 10% palladium on carbon (95 mg,5 wt%) were weighed into a 100mL two-necked flask equipped with a magnetic stirrer, 30mL of ethyl acetate and 10mL of methanol were added, the displacement of hydrogen was performed several times, and the reaction was carried out at 40℃for 1 to 2 hours. After the reaction is completed, the diatomite is filtered to remove palladium carbon, filter residues are leached by ethyl acetate,the filtrate was collected and ethyl acetate was removed by rotary evaporation to give crude product. The crude product was purified by column chromatography on silica gel to give a red-black solid (863 mg,3.1mmol, 75.6%). 1 H NMR(400MHz,CDCl 3 )δ9.27(d,J＝8.8Hz,1H),8.26(d,J＝8.8Hz,1H),7.72(d,J＝8.8Hz,1H),7.55(dd,J＝8.8,6.8Hz,1H),7.38(d,J＝6.8Hz,1H),4.96(t,J＝9.6Hz,1H),4.42(dd,J＝9.6,6.4Hz,1H),3.69–3.60(m,1H),2.68(s,3H),1.41(d,J＝6.8Hz,3H)； 13 C NMR(101MHz,CDCl 3 )δ184.35,175.75,170.63,135.04,134.80,132.15,131.98,130.47,128.90,128.26,126.10,125.08,120.37,118.41,81.71,34.77,19.94,18.90。

Claims (12)

1. The synthesis method of the dihydrotanshinone I is characterized by comprising the following steps of:
(a) In a solvent A, under the action of a palladium catalyst and hydrogen, reducing the ketocarbonyl of a compound 1 (tanshinone I) into phenol, and then under the action of alkali, carrying out nucleophilic reaction with benzyl halide to obtain a compound 2;
(b) Oxidizing compound 2 to compound 3 in solvent B under the action of an oxidizing agent;
(c) Oxidizing the compound 3 into a compound 4 in a mixed solvent C under the action of an oxidant and acid;
(d) In a solvent D, under the action of alkali, performing nucleophilic reaction on the compound 4 and a methylation reagent to obtain a compound 5;
(e) Reducing the compound 5 into a compound 6 in a mixed solvent E under the action of magnesium chips or magnesium powder, ammonium chloride and methanol;
(f) Hydrolyzing the compound 6 into a compound 7 in a mixed solvent F under the action of alkali;
(g) Salifying a compound 7 and chiral amine in a solvent G, heating and dissolving the obtained salt in the solvent G', standing and precipitating the salt at a certain temperature, recrystallizing for a plurality of times, and acidifying the obtained salt to obtain a compound 8;
(h) Reducing compound 8 to compound 9 in solvent H under the action of a reducing agent;
(i) In a solvent I, under the action of alkali and 4-dimethylaminopyridine, reacting the compound 9 with p-toluenesulfonyl chloride to obtain a compound 10;
(j) Removing the p-toluenesulfonate group of the compound 10 in a solvent J under the action of a reducing agent to obtain a compound 11;
(k) In a solvent K, under the action of a palladium catalyst and hydrogen, removing benzyl from the compound 11 to obtain dihydrotanshinone I;
the synthetic route is as follows:
2. the method of claim 1, wherein in step (a),
the solvent A is one of N, N-dimethylformamide, N-dimethylacetamide or tetrahydrofuran; the ratio of the volume of the solvent A to the mole number of the compound 1 is 1-5 mL/1 mmol;
the palladium catalyst is palladium carbon or palladium hydroxide carbon; the mass ratio of the palladium catalyst to the compound 1 is 2-10:100;
The alkali is one of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine or N-methylmorpholine; the molar ratio of the alkali to the compound 1 is 2-5:1;
the benzyl halide is benzyl chloride or benzyl bromide, preferably benzyl chloride; the molar ratio of the halogenated benzyl to the compound 1 is 2.0-5.0:1, preferably 2.5:1;
the reaction temperature for reducing the ketone carbonyl of the compound 1 into phenol is 25-45 ℃; the reaction time for reducing the ketocarbonyl of the compound 1 into phenol is 2-8 hours;
the reaction temperature for nucleophilic reaction with benzyl halide is 25-90 ℃, preferably 75 ℃; the reaction time for nucleophilic reaction with benzyl halide is 3-10 hours, preferably 5-6 hours;
the step of preparing compound 2 by protecting compound 1 with benzyl group includes: dissolving a compound 1 and a palladium catalyst in a solvent A, replacing hydrogen for a plurality of times, and reacting at 25-45 ℃ in a hydrogen atmosphere; after the reaction liquid is changed from red to colorless and clear, adding the reaction liquid into a system containing alkali, then adding the benzyl halide, and carrying out nucleophilic reaction at 25-90 ℃ under argon atmosphere;
the post-treatment method of the reaction liquid obtained by protecting the compound 1 by benzyl to prepare the compound 2 is as follows: after the reaction is completed, filtering the obtained reaction solution by using diatomite to remove solids, leaching filter residues by using ethyl acetate, adding water and ethyl acetate into the filtrate, separating the solution, and extracting a water layer by using ethyl acetate; combining the organic layers, and sequentially washing with water, saturated saline water, drying and spin drying to obtain a crude product; petroleum ether and ethyl acetate are added into the crude product, stirred for 10-15 minutes, and filtered to obtain the compound 2.
3. The method for synthesizing dihydrotanshinone I according to claim 1 wherein in step (b),
the solvent B is one of dichloromethane, tetrahydrofuran or dioxane, preferably dioxane; the ratio of the volume of the solvent B to the mole number of the compound 2 is 1-5 mL to 1mmol;
the oxidant is selenium dioxide; the molar ratio of the oxidant to the compound 2 is 2-10:1;
the reaction temperature for oxidizing the compound 2 to the compound 3 is 80-120 ℃, preferably 100-110 ℃; the reaction time for oxidizing compound 2 to compound 3 is 18 to 36 hours, preferably 24 to 30 hours;
the method for working up the reaction liquid obtained by oxidizing compound 2 to compound 3 is as follows: after the reaction is completed, adding water and dichloromethane, separating liquid, and extracting a water layer by using dichloromethane; combining the organic layers, and sequentially washing with water, saturated saline water, drying and spin drying to obtain a crude product; petroleum ether and ethyl acetate are added into the crude product, stirred for 10-15 minutes, and filtered to obtain the compound 3.
4. The method for synthesizing dihydrotanshinone I according to claim 1 wherein in step (c),
the mixed solvent C is a mixed solvent of tetrahydrofuran, water and tertiary butanol, and the volume ratio is 1-10:1-3:1, preferably 6-9:3:1; the ratio of the volume of the mixed solvent C to the mole number of the compound 3 is 10-20 mL/1 mmol;
The oxidant is sodium chlorite; the molar ratio of the oxidant to the compound 3 is 1.5-5.0:1, preferably 3.0:1;
the acid is sulfamic acid, resorcinol, sodium dihydrogen phosphate or potassium dihydrogen phosphate, preferably sulfamic acid; the molar ratio of the acid to the compound 3 is 1.5-5.0:1, preferably 3.0:1;
the reaction temperature for oxidizing the compound 3 into the compound 4 is-20-0 ℃, preferably-10-5 ℃; the reaction time for oxidizing compound 3 to compound 4 is 10 to 30 minutes, preferably 15 to 20 minutes;
the step of oxidizing compound 3 to compound 4 includes: dissolving the compound 3 and acid in a mixed solvent C, and stirring for 10-20 minutes at the temperature of-20-0 ℃; slowly dripping an aqueous solution of an oxidant, and reacting at the temperature of-20 to 0 ℃ after the dripping is finished;
the method for working up the reaction liquid obtained by oxidizing compound 3 to compound 4 is as follows: after the reaction is completed, dropwise adding sodium sulfite aqueous solution to quench redundant oxidant at-20-0 ℃; after the dripping is finished, ethyl acetate is added, and after liquid separation, the water layer is extracted by ethyl acetate; the organic layers are combined, washed by water, saturated brine, dried and spin-dried to obtain a crude product, petroleum ether and ethyl acetate are added into the crude product, and the mixture is stirred for 10 to 15 minutes and filtered to obtain the compound 4.
5. The method of claim 1, wherein in step (d),
the solvent D is one of dichloromethane, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide or N, N-dimethylacetamide; the ratio of the volume of the solvent D to the mole number of the compound 4 is 1-5 mL/1 mmol;
the alkali is one of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine or N-methylmorpholine; the molar ratio of the alkali to the compound 4 is 1.5-5.0:1;
the methylation reagent is potassium iodide or dimethyl sulfate; the molar ratio of the methylation reagent to the compound 4 is 2-10:1, preferably 4-6:1;
the reaction temperature for methylation of compound 4 to compound 5 is 25-60 ℃, preferably 45-55 ℃; the reaction time for methylation of compound 4 to compound 5 is 1.5 to 8.0 hours, preferably 3.0 to 5.0 hours;
the step of methylation of compound 4 to compound 5 comprises: dissolving the compound 4 and alkali in a solvent D, and stirring for 10-20 minutes at 25 ℃; then adding a methylating reagent dropwise, and reacting at 25-60 ℃ after finishing the dropwise addition;
the post-treatment method of the reaction liquid obtained by methylation of the compound 4 into the compound 5 is as follows: after the reaction is completed, filtering to remove solids, leaching filter residues with ethyl acetate, and collecting filtrate to spin dry to obtain a crude product; petroleum ether and ethyl acetate are added into the crude product, stirred for 10-15 minutes, and filtered to obtain the compound 5.
6. The method for synthesizing dihydrotanshinone I according to claim 1 wherein in step (e),
the mixed solvent E is a mixed solvent of anhydrous tetrahydrofuran and anhydrous methanol, and the volume ratio is 1-5:1, preferably 4:1; the ratio of the volume of the mixed solvent E to the mole number of the compound 5 is 15-30 mL/1 mmol;
the molar ratio of the magnesium chips or the magnesium powder to the compound 5 is 10-30:1, preferably 20:1;
the molar ratio of the ammonium chloride to the compound 5 is 3-8:1, preferably 5-6:1;
the reaction temperature for reducing the compound 5 to the compound 6 is 0-45 ℃, preferably 25-30 ℃; the reaction time for reducing compound 5 to compound 6 is 1 to 5 hours, preferably 2 to 3 hours;
the step of reducing compound 5 to compound 6 includes: dissolving a compound 5, magnesium chips or magnesium powder and ammonium chloride in a mixed solvent E, and stirring and reacting at 0-45 ℃ under an argon atmosphere;
the method for working up the reaction mixture obtained by reducing compound 5 to compound 6 is as follows: after the reaction is completed, adding an ammonium chloride aqueous solution at 0-5 ℃ until the solution is clear; adding ethyl acetate, separating, extracting the water layer with ethyl acetate, mixing the organic layers, washing with water, saturated saline water, drying, and spin drying to obtain crude product; petroleum ether and ethyl acetate are added into the crude product, stirred for 10-15 minutes, and filtered to obtain the compound 6.
7. The method for synthesizing dihydrotanshinone I according to claim 1 wherein in step (f),
the mixed solvent F is a mixed solvent of tetrahydrofuran, methanol and water, and the volume ratio is 5-3:3-1:1; the ratio of the volume of the mixed solvent F to the mole number of the compound 6 is 3-10 mL/1 mmol;
the alkali is one of lithium hydroxide, sodium hydroxide or potassium hydroxide; the molar ratio of the alkali to the compound 6 is 1.5-5.0:1, preferably 2.0-3.0:1;
the reaction temperature for hydrolyzing the compound 6 into the compound 7 is 25-60 ℃, preferably 40-50 ℃; the reaction time for hydrolyzing the compound 6 to the compound 7 is 1 to 5 hours, preferably 2 to 3 hours;
the step of hydrolyzing compound 6 to compound 7 includes: dissolving the compound 6 in the mixed solvent E, dropwise adding an aqueous solution of alkali, and reacting at 25-60 ℃;
the post-treatment method of the reaction liquid obtained by hydrolyzing the compound 6 into the compound 7 is as follows: after the reaction is completed, removing the organic solvent by rotary evaporation; adding hydrochloric acid into the concentrated solution for acidification, adding dichloromethane, separating, extracting a water layer with dichloromethane, combining organic layers, and sequentially performing saturated saline washing, drying and spin drying to obtain a crude product; petroleum ether and ethyl acetate are added into the crude product, stirred for 10-15 minutes, and filtered to obtain the compound 7.
8. The method for synthesizing dihydrotanshinone I according to claim 1 wherein in step (g),
the solvent G is one of dichloromethane, ethyl acetate, tetrahydrofuran, dioxane, methanol, ethanol or isopropanol; the ratio of the volume of the solvent G to the mole number of the compound 7 is 10-40 mL/1 mmol;
the solvent G' used for recrystallization is one or more of dichloromethane, ethyl acetate, tetrahydrofuran, methanol, ethanol and isopropanol, and is preferably a single solvent isopropanol or a mixed solvent of isopropanol and methanol with the volume ratio of 50-200:1; the ratio of the mol number of the solvent G' to the compound 7 used for recrystallization is 25-60 mL:1mmol;
the chiral amine is one of (R) - (+) -alpha-methylbenzylamine, (S) - (-) -alpha-methylbenzylamine, (R) - (+) -N-benzyl-1-phenethylamine, (S) - (-) -N-benzyl-1-phenethylamine, (R) - (-) -2-amino-1-butanol, (S) - (+) -2-amino-1-butanol, (R) - (-) -2-amino-3-methyl-1-butanol, (S) - (+) -2-amino-3-methyl-1-butanol, (R) - (-) -2-amino-4-methyl-1-pentanol or (S) - (+) -2-amino-4-methyl-1-pentanol), and is preferably (R) - (+) -alpha-methylbenzylamine; the molar ratio of the chiral amine to the compound 7 is 1.05-1.50:1;
The reaction temperature for salifying the compound 7 and chiral amine is 25-50 ℃, preferably 25-30 ℃; the reaction time for salifying the compound 7 and chiral amine is 10-30 minutes, preferably 15-25 minutes;
the temperature of heating and dissolving the obtained salt is 80-130 ℃, preferably 100-115 ℃;
the temperature for standing and separating out the obtained salt is 25-65 ℃, preferably 30-50 ℃; the time for standing and precipitating the obtained salt is 1.0-6.0 hours, preferably 1.5-4.0 hours;
the number of times of recrystallization is 1 to 4 times, preferably 2 times;
the salifying step of the compound 7 and chiral amine comprises the following steps: dissolving the compound 7 in a solvent G, adding chiral amine, reacting at 25-50 ℃, and removing the solvent by rotary evaporation after full salification to obtain the salt of the compound 7;
the step of recrystallizing and acidifying the salt of compound 7 with chiral amine to obtain compound 8 comprises: heating and dissolving a salt formed by the compound 7 and chiral amine in a solvent G'; after complete dissolution, keeping the solution at 25-65 ℃ for standing precipitation, and filtering to obtain salt; recrystallizing for 1-4 times according to the method, adding ethyl acetate into salt obtained by recrystallization, acidifying with hydrochloric acid, and extracting a water layer with ethyl acetate; the organic layers were combined, washed with saturated brine, dried and spin-dried in this order to give compound 8.
9. The method for synthesizing dihydrotanshinone I according to claim 1 wherein in step (h),
the solvent H is one of anhydrous tetrahydrofuran, anhydrous dioxane or anhydrous ethanol; the ratio of the volume of the solvent H to the mole number of the compound 8 is 3-10 mL/1 mmol;
the reducing agent is one of lithium aluminum hydride, sodium borohydride or borane tetrahydrofuran complex, and is preferably lithium aluminum hydride; the mol ratio of the reducing agent to the compound 8 is 1.5-3.5:1;
the reaction temperature for reducing the compound 8 to the compound 9 is-20-25 ℃, preferably-10-5 ℃; the reaction time for reducing the compound 8 to the compound 9 is 0.5-2 hours;
the step of reducing compound 8 to compound 9 includes: dissolving a compound 8 in a mixed solvent H, adding a reducing agent, and reacting at-20-25 ℃ in an argon atmosphere;
the method for working up the reaction mixture obtained by reducing compound 8 to compound 9 is as follows: after the reaction is completed, adding saturated ammonium chloride aqueous solution or dilute hydrochloric acid to quench the reaction, adding ethyl acetate, separating the liquid, and extracting the water layer with ethyl acetate; combining the organic layers, and sequentially washing with saturated saline, drying and spin-drying to obtain a crude product; purifying the crude product by silica gel column chromatography to obtain a compound 9; the silica gel for silica gel column chromatography is 200-300 meshes of silica gel, and the eluent is petroleum ether with the volume ratio: dichloromethane: ethyl acetate=8-10:1-2:1 mixed solvent.
10. The method for synthesizing dihydrotanshinone I according to claim 1, wherein in step (I), the solvent I is anhydrous dichloromethane or anhydrous tetrahydrofuran; the ratio of the volume of the solvent I to the mole number of the compound 9 is 3-15 mL/1 mmol;
the alkali is one of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine or N-methylmorpholine; the molar ratio of the alkali to the compound 9 is 2-5:1;
the molar ratio of the 4-dimethylaminopyridine to the compound 9 is 0.1-1:1, preferably 0.4-0.6:1;
the molar ratio of the tosyl chloride to the compound 9 is 2-10:1, preferably 5-8:1;
the reaction temperature for the sulfonic acid esterification of the compound 9 into the compound 10 is 25-50 ℃, preferably 35-45 ℃; the reaction time for the sulfonation of the compound 9 to the compound 10 is 1 to 5 hours, preferably 2 to 3 hours;
the step of sulfonating compound 9 to compound 10 comprises: dissolving a compound 9, p-toluenesulfonyl chloride and 4-dimethylaminopyridine in a solvent H, and reacting at 25-50 ℃ under an argon atmosphere;
the post-treatment method of the reaction liquid obtained by the sulfonic acid esterification of the compound 9 into the compound 10 is as follows: after the reaction is completed, adding water, separating liquid, and extracting a water layer by using dichloromethane; combining the organic layers, sequentially washing with water, saturated saline water, drying and spin drying to obtain a crude product, and purifying the crude product by silica gel column chromatography to obtain a compound 10; the silica gel for silica gel column chromatography is 200-300 meshes of silica gel, and the eluent is petroleum ether with the volume ratio: dichloromethane: ethyl acetate=18-20:1-2:1 mixed solvent.
11. The method for synthesizing dihydrotanshinone I according to claim 1 wherein in step (j),
the solvent J is anhydrous dichloromethane, anhydrous tetrahydrofuran or anhydrous dioxane, and preferably anhydrous tetrahydrofuran; the ratio of the volume of the solvent J to the mole number of the compound 10 is 3-15 mL/1 mmol;
the reducing agent is one of lithium aluminum hydride, sodium borohydride, lithium borohydride or triethylsilane, and is preferably lithium aluminum hydride; the molar ratio of the reducing agent to the compound 10 is 2-10:1, preferably 4-5:1;
the reaction temperature for reducing the compound 10 to the compound 11 is 0-60 ℃, preferably 35-45 ℃; the reaction time for reducing compound 10 to compound 11 is 0.5 to 5 hours, preferably 1 to 2 hours;
the step of sulfonating compound 9 to compound 10 comprises: dissolving a compound 9, p-toluenesulfonyl chloride and 4-dimethylaminopyridine in a solvent H, and reacting at 25-50 ℃ under an argon atmosphere;
the post-treatment method of the reaction liquid obtained by reducing the compound 10 to the compound 11 is as follows: after the reaction is completed, adding saturated ammonium chloride aqueous solution or dilute hydrochloric acid to quench the rest reducing agent, adding ethyl acetate, separating liquid, and extracting a water layer by using ethyl acetate; combining the organic layers, and sequentially washing with saturated saline, drying and spin-drying to obtain a crude product; purifying the crude product by silica gel column chromatography to obtain a compound 11; the silica gel for silica gel column chromatography is 200-300 meshes of silica gel, and the eluent is petroleum ether with the volume ratio: dichloromethane: ethyl acetate=18-20:1-2:1 mixed solvent.
12. The method for synthesizing dihydrotanshinone I according to claim 1 wherein in step (k),
the solvent K is one or more of tetrahydrofuran, ethyl acetate or methanol, and is preferably a mixed solvent of ethyl acetate and methanol in a volume ratio of 3:1; the ratio of the volume of the solvent K to the mole number of the compound 11 is 3-15 mL/1 mmol;
the palladium catalyst is palladium carbon or palladium hydroxide carbon; the mass ratio of the palladium catalyst to the compound 11 is 2-10:100, preferably 5:100;
the reaction temperature for debenzylating the compound 11 to the compound of formula (I) is 25-50 ℃, preferably 35-45 ℃; the reaction time for debenzylating compound 11 to the compound of formula (I) is 0.5 to 5 hours, preferably 1 to 2 hours;
the step of debenzylating compound 11 to a compound of formula (I) comprises: dissolving a compound 11 and a palladium catalyst in a solvent K, replacing hydrogen for a plurality of times, and reacting at 25-50 ℃ in a hydrogen atmosphere;
the post-treatment method of the reaction liquid obtained by debenzylating the compound 11 into the compound of the formula (I) is as follows: after the reaction is completed, the diatomite is filtered to remove the palladium catalyst, filter residues are leached by ethyl acetate, filtrate is collected, and the ethyl acetate is removed by rotary evaporation to obtain a crude product; purifying the crude product by silica gel column chromatography to obtain a compound of formula (I), namely dihydrotanshinone I; the silica gel for silica gel column chromatography is 200-300 meshes of silica gel, and the eluent is methylene dichloride with the volume ratio: methanol=40 to 50:1.
CN202310328640.4A 2023-03-27 2023-03-27 Synthesis method of dihydrotanshinone I Pending CN116514896A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310328640.4A CN116514896A (en) 2023-03-27 2023-03-27 Synthesis method of dihydrotanshinone I

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310328640.4A CN116514896A (en) 2023-03-27 2023-03-27 Synthesis method of dihydrotanshinone I

Publications (1)

Publication Number Publication Date
CN116514896A true CN116514896A (en) 2023-08-01

Family

ID=87396666

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310328640.4A Pending CN116514896A (en) 2023-03-27 2023-03-27 Synthesis method of dihydrotanshinone I

Country Status (1)

Country Link
CN (1) CN116514896A (en)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1394870A (en) * 2001-07-05 2003-02-05 北京天纯维通生物技术有限公司 Method for separating and purifying tanshinone
CN102702302A (en) * 2012-06-07 2012-10-03 四川大学 Tanshinone class I derivant and synthesizing method and application thereof
CN108379273A (en) * 2018-03-08 2018-08-10 广州神农生物技术有限公司 Dihydrotanshinone I is preparing application and preparation method in treating multidrug-resistant carcinoma drug
CN109485691A (en) * 2017-09-12 2019-03-19 上海交通大学医学院附属新华医院 Tanshinone compound and its for treating angiomatous purposes
CN113230261A (en) * 2021-04-13 2021-08-10 南方医科大学 Application of dihydrotanshinone I or pharmaceutically acceptable salt thereof in preparation of anti-coronavirus medicines
CN114315952A (en) * 2022-01-18 2022-04-12 浙江大学 Tanshinone I derivative, preparation method and application thereof
CN115074375A (en) * 2022-03-09 2022-09-20 中国医学科学院药用植物研究所 Salvia 2-oxoglutarate-dependent dioxygenase gene and application thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1394870A (en) * 2001-07-05 2003-02-05 北京天纯维通生物技术有限公司 Method for separating and purifying tanshinone
CN102702302A (en) * 2012-06-07 2012-10-03 四川大学 Tanshinone class I derivant and synthesizing method and application thereof
CN109485691A (en) * 2017-09-12 2019-03-19 上海交通大学医学院附属新华医院 Tanshinone compound and its for treating angiomatous purposes
CN108379273A (en) * 2018-03-08 2018-08-10 广州神农生物技术有限公司 Dihydrotanshinone I is preparing application and preparation method in treating multidrug-resistant carcinoma drug
CN113230261A (en) * 2021-04-13 2021-08-10 南方医科大学 Application of dihydrotanshinone I or pharmaceutically acceptable salt thereof in preparation of anti-coronavirus medicines
CN114315952A (en) * 2022-01-18 2022-04-12 浙江大学 Tanshinone I derivative, preparation method and application thereof
CN115074375A (en) * 2022-03-09 2022-09-20 中国医学科学院药用植物研究所 Salvia 2-oxoglutarate-dependent dioxygenase gene and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JIAMING LI等: "Scaffold Hybrid of the Natural Product Tanshinone I with Piperidine for the Discovery of a Potent NLRP3 Inflammasome Inhibitor", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 66, 14 February 2023 (2023-02-14), pages 2946 *
YING MA等: "Expansion within the CYP71D subfamily drives the heterocyclization of tanshinones synthesis in Salvia miltiorrhiza", 《NATURE COMMUNICATIONS》, 29 January 2021 (2021-01-29), pages 1 - 11 *

Similar Documents

Publication Publication Date Title
WO2003016270A2 (en) Selective estrogen receptor modulators
CN113943336B (en) Method for synthesizing cholesterol by taking BA as raw material
CN108659041B (en) Phosphine ligand compound based on tetramethyl spiroindane skeleton, intermediate thereof, preparation method and application
Barber et al. Conversion of thebaine to codeine
CN111116677A (en) Preparation method and application of metal-organic framework structure compound with chiral pore structure
CN115368272A (en) Preparation method of 4-cyano-2-methoxybenzaldehyde
CN113735847B (en) Synthetic preparation method of berberine hydrochloride
CN102993181A (en) Preparation method of esomeprazole and preparation method of esomeprazole salt
CN109942593A (en) A kind of total synthesis method of racemization hanfangchin A
CN116514896A (en) Synthesis method of dihydrotanshinone I
CN110294730B (en) Difluoromethyl sulfuration flavonoid compound and preparation method thereof
CN112300073B (en) Preparation method of isoquinoline derivative
CN107880004B (en) Preparation method of 5-phenoxyphthalide
CN111039868A (en) Preparation method of cisatracurium besilate impurity C benzene sulfonate
CN113999164B (en) Preparation method of halofuginone intermediate trans-N-benzyloxycarbonyl- (3-hydroxy-2-piperidinyl) -2-propanone
CN114057625B (en) C2-acyloxy-3-indolinone derivative and preparation method and application thereof
CN101805339B (en) Entecavir compound preparation method
CN111377850B (en) Chiral N-substituted-3,3-difluoro-4-hydroxypiperidine derivative and preparation method thereof
CN111100042B (en) Preparation method of 2-methoxy-5-sulfonamide benzoic acid
CN111018928B (en) Synthetic method and application of gastrodin hemihydrate
CN109232544B (en) Preparation method of prucalopride
CN112250586A (en) Preparation method of terbutaline sulfate and B crystal form thereof
CN105732613B (en) A kind of synthetic method of 9 demethyl (+) α dihydrotetrabenazineins
CN105622356A (en) Helicene diphenol hydride, method for preparing same and application of helicene diphenol hydride
CN100432044C (en) New process for preparing levo-albuterol

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination