Preparation method of cryptotanshinone

Abstract

The invention relates to a preparation method of cryptotanshinone, which comprises the following steps: (1) carrying out ring opening and rearrangement reaction on cryptotanshinone under the action of an alkali reagent to generate salt of the cryptotanshinone; and (2) carrying out neutralization reaction on the salt of the neocryptotanshinone under the action of an acid reagent to obtain the neocryptotanshinone. According to the method, one-pot reaction is adopted, separation steps are few, operation is easy, the product quality and purity of the neocryptotanshinone are improved, the product yield is high, meanwhile, reaction conditions are easy to control, the production cost is low, and the method is environmentally friendly and especially suitable for industrial mass production.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing a new cryptotanshinone. Background Art

[0002] Danshen is an important herb in traditional Chinese medicine and is widely used in Asia to treat various diseases such as inflammation, diabetes, atherosclerosis, allergic asthma and angina pectoris. It is especially used for patients with blood stasis and heat in gynecology, internal medicine and surgery.

[0003] Currently, most of the injections related to salvia miltiorrhiza are salvia miltiorrhiza polyphenolates (i.e., polyphenolates with salvia miltiorrhiza magnesium acetate as the main component are the most important active ingredients of salvia miltiorrhiza for treating cardiovascular diseases). The preparation method is to extract them from the plant salvia miltiorrhiza. Although they have been purified, in addition to the main ingredient, magnesium salvia miltiorrhiza acid B, they still contain other homologues (such as magnesium lithospermate, sodium rosmarinate, dipotassium salvia miltiorrhiza acetate, potassium danshen and dipotassium lithospermate, etc.), which may be the reason for the relatively large side effects of salvia miltiorrhiza polyphenolate injection in clinical practice.

[0004] It can be seen that due to the high structural similarity between homologues, it is difficult to obtain high-purity (high-quality) effective components of Salvia miltiorrhiza by extraction alone. Therefore, it is necessary to prepare high-purity effective components of Salvia miltiorrhiza through chemical synthesis. Taking neocryptoshinone as an example, due to its potential application value in the clinical treatment of cardiovascular diseases and its low content in plants (less than 1%), it is difficult to achieve large-scale production through extraction. At present, some literatures have reported its synthesis, but none of them are suitable for industrial production.

[0005] In 1995, Danheiser, RJ research team reported a synthetic route for (+)-Neocryptotanshinon (Danheiser, RJ; David S. Casebier, DS and Firooznia, FJ Org. Chem. 1995, 60, 8341-8350). As shown in the following reaction scheme, this route uses anisole as the starting material and obtains the target product through a series of reactions. The total yield of this route is 5-10%. This route has many steps, some of which have harsh reaction conditions (such as low temperature -78°C, anhydrous and oxygen-free, photocatalytic conditions, etc.), are not easy to operate, and involve flammable and dangerous reagents such as tetramethylethylenediamine (TMEDA), n-butyllithium (n-BuLi), tetrahydrofuran (THF), pyridine, benzene (PhH), carbon monoxide (CO), etc., explosive and dangerous reagents such as methanesulfonyl azide (MsN3), corrosive reagents such as trifluoroacetic anhydride (TFEA), aluminum chloride (AlCl3), etc.; it involves the use of precious metal catalysts such as palladium complex catalysts (PdCl2 (dppf)), the conditions of metal catalytic reactions are harsh, the operation is complicated and the post-processing is troublesome. At the same time, transition metal-catalyzed reactions encounter bottlenecks when the reaction is scaled up (yield and ee value decreases, etc.), and palladium complex catalysts cannot be recovered, and the amount of three wastes discharged is high. The reaction temperature is large, which is not conducive to environmental protection; in the diazoacetylation reaction, carbon monoxide gas needs to be used, and a relatively high temperature (90°C) and high pressure (50 psi, equivalent to 3.5 bar) are used, which has a relatively high safety risk and high requirements for equipment; in the photocatalytic (HV) ring-closing reaction, the mixed solution of α-diazo ketone, siloxy acetylene compound and benzene needs to be evenly distributed between four high-silica glass tubes with a length of 20 cm and an inner diameter of 15 mm equipped with rubber diaphragms, and the reaction mixture is degassed at low temperature (at -196°C and a vacuum degree of about 0.1 mmHg, three "freeze-vacuum-thaw or thaw three-step cycles" are performed, and the operation is performed under a vacuum pipeline to degas the solution), and then irradiated with 254 nm light for 24 hours in a Rayonet photoreactor. The conditions of this step of the reaction are relatively harsh, the operation is difficult, and the requirements for equipment are also high. Therefore, it is difficult to achieve large-scale industrial production, and it is even more difficult to achieve environmentally friendly green synthesis, and its production cost is also difficult to reduce.

[0006]

[0007] In 2019, Xie Ping's research group reported the synthesis of cryptotanshinone and isocryptotanshinone. The synthesis route of the key intermediate neocryptotanshinone ((+)-Neocryptotanshinon) involved (Xiang Shi, Xiaoyu Liu, Feilong Yang, Yong Wang, Zhenwei Wang, Xiaozhen Jiao, Ping Xie, Tetrahedron 2019, 75, 3962-3967) is shown in the following reaction route. This route uses 3,4-dihydrobenzopyrone as the starting material and obtains the target product through a series of reactions. The total yield of this route is less than 2%. This route also has the disadvantages of complex reaction steps, harsh reaction conditions (such as low temperature -78℃ for 25h, anhydrous and oxygen-free conditions), involving flammable and dangerous reagents such as acetone, tetrahydrofuran (THF), pyridine, toluene, pivaloyl chloride (PivCl), ether (Et2O), etc., involving toxic reagent iodomethane, and involving precious metal catalysts such as Pd reagent (bistriphenylphosphine palladium dichloride). Although the reaction conditions of the last step of this route are simple and easy, due to the unavailability and high price of compound 21 (compound 21 is currently mainly obtained by extraction, and its market price is more than 3 times more expensive than the target product new cryptotanshinone, and only 1-5mg packaging is available, and it cannot be supplied on a large scale), it is obviously not feasible to use compound 21 as the starting material for industrial production of new cryptotanshinone. Therefore, this synthetic route is also difficult to achieve industrial large-scale production, and it is even more difficult to achieve environmentally friendly green synthesis, and its production cost is also difficult to reduce.

[0008]

[0009] In summary, the above synthetic route is difficult to carry out industrial production, and it is very difficult to carry out small and pilot tests. Therefore, a preparation method of a new cryptotanshinone with simple operation, few purification steps, green environmental protection and high yield is provided, so that it can be applied to industrial production and has good industrial prospects. Summary of the invention

[0010] In order to solve the above technical problems, the present invention provides a method for preparing a new cryptotanshinone. The present invention uses commercially available and relatively inexpensive cryptotanshinone as a starting material, and obtains the target compound, new cryptotanshinone, through a two-step reaction (ring-opening reaction + rearrangement reaction) and a one-step one-pot reaction method, which not only simplifies the synthesis route and reduces the production cost, but also effectively improves the yield and purity of the product.

[0011] To achieve this object, the present invention adopts the following technical solutions:

[0012] The present invention provides a method for preparing a new cryptotanshinone, which comprises the following steps:

[0013] (1) Cryptotanshinone undergoes ring opening and rearrangement reaction under the action of an alkaline reagent to generate a new cryptotanshinone salt;

[0014] (2) The salt of neocryptotanshinone undergoes a neutralization reaction under the action of an acid reagent to obtain neocryptotanshinone.

[0015] In the present invention, the reaction formula of the preparation method is as follows:

[0016]

[0017] Among them, compound 1 is cryptotanshinone and compound 3 is neocrypttanshinone.

[0018] The present invention uses commercially available and relatively inexpensive cryptotanshinone as a starting material, and obtains the target compound neocrypttanshinone through a two-step reaction (ring-opening reaction + rearrangement reaction) and a one-step one-pot reaction method, which not only simplifies the synthesis route, but also effectively improves the yield and purity of the product. At the same time, the preparation method has a mature and stable reaction, is easy to operate, and the reagents used are simple and easy to obtain, avoiding asymmetric reagents and precious metals, has good economic benefits, is environmentally friendly, and is suitable for industrial production.

[0019] Preferably, the alkaline agent includes any one of potassium hydroxide, sodium hydroxide, sodium methoxide or sodium ethoxide, or a combination of at least two thereof.

[0020] Preferably, the acid reagent includes any one of hydrochloric acid, sulfuric acid or glacial acetic acid, or a combination of at least two of them.

[0021] Preferably, the molar ratio of cryptotanshinone, the alkaline agent and the acid agent is 1:(1-20):(0.8-20), preferably 1:(2-3):(2-3).

[0022] The above numerical value (1 to 20) may be, for example, 2, 2.5, 3, 5, 10, 15, 18, etc.

[0023] The above numerical value (0.8 to 20) may be, for example, 2, 2.5, 3, 5, 10, 15, 18, etc.

[0024] In the present invention, if the amount of the alkali reagent is too small, the reaction time will be too long and the reaction efficiency will be too low. The synthesis efficiency can be further improved within the dosage range specified in the present invention.

[0025] Preferably, in step (1), the reaction is carried out in an organic solvent.

[0026] Preferably, the organic solvent includes any one of ethanol, methanol or propanol, or a combination of at least two of them.

[0027] Preferably, after the reaction, the process further comprises the steps of reducing pressure and concentrating to recover the organic solvent, adding water to dissolve, extracting with an organic solvent, and concentrating under reduced pressure for the second time to recover the organic solvent.

[0028] Preferably, the organic solvent used for the extraction includes any one of dichloromethane, ethyl acetate or tetrahydrofuran, or a combination of at least two thereof, and dichloromethane is more preferred.

[0029] In the present invention, the organic solvent recovered by reduced pressure concentration can be reused in the reaction system, so as to realize the reuse of the solvent and reduce the production cost. The unreacted cryptotanshinone raw material and its fat-soluble byproducts can be removed by extraction treatment to obtain an aqueous solution of a new cryptotanshinone salt, and the organic solvent used for extraction can also be recovered and reused, further reducing the production cost.

[0030] Preferably, in step (1), the reaction temperature is -20 to 40°C (for example, it can be -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, etc.), and the reaction time is 1 to 24h (for example, it can be 2h, 4h, 8h, 16h, 20h, etc.).

[0031] Further preferably, in step (1), the reaction temperature is 0 to 30° C., and the reaction time is 1 to 6 hours.

[0032] Preferably, in step (2), the reaction is carried out in an aqueous solution.

[0033] Preferably, in step (2), the reaction temperature is -20 to 40°C (for example, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, etc.), and the reaction time is 0.5 to 12 h (for example, 2 h, 4 h, 6 h, 8 h, 10 h, etc.).

[0034] More preferably, in step (2), the reaction temperature is 10 to 30° C., and the reaction time is 0.5 to 3 h.

[0035] Preferably, in step (2), the reaction further includes a post-treatment process.

[0036] Preferably, the post-treatment process includes: extracting the reaction solution, concentrating the extract, filtering and washing with a silica gel pad, concentrating the filtrate and recrystallizing to obtain the neocrypttanshinone.

[0037] In the present invention, water-soluble salts can be removed by extraction treatment, and organic solvent can be recovered by concentration to obtain a crude product. The yield of the crude product of the preparation method of the present invention can be increased to more than 85%. The obtained crude product can be purified by filtration-recrystallization to obtain a high-purity product. The purity of the product obtained by the preparation method of the present invention is greater than 99.0%.

[0038] Preferably, the solvent used for the extraction includes any one of ethyl acetate, dichloromethane, tetrahydrofuran or methanol, or a combination of at least two of them, preferably a combination of dichloromethane and methanol.

[0039] Preferably, the extraction is carried out by gradient extraction. For example, dichloromethane is first used for extraction, and then a mixed solvent of dichloromethane and methanol with a volume ratio of (40-1):1 (for example, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1, etc.) is used for gradient extraction.

[0040] In a specific embodiment, the extraction is carried out in sequence with dichloromethane, dichloromethane and methanol in a volume ratio of 10:1, dichloromethane and methanol in a volume ratio of 5:1, and dichloromethane and methanol in a volume ratio of 1:1.

[0041] In a specific embodiment, the extraction can be performed sequentially using dichloromethane, dichloromethane and methanol in a volume ratio of 20:1, dichloromethane and methanol in a volume ratio of 10:1, and dichloromethane and methanol in a volume ratio of 5:1.

[0042] In a specific embodiment, the extraction can be carried out in sequence using dichloromethane, dichloromethane and methanol in a volume ratio of 40:1, dichloromethane and methanol in a volume ratio of 10:1, dichloromethane and methanol in a volume ratio of 5:1, dichloromethane and methanol in a volume ratio of 3:1, and dichloromethane and methanol in a volume ratio of 1:1.

[0043] In the present invention, when the extraction solvent is a dual-system solvent of dichloromethane and methanol for gradient extraction, it is beneficial to improve the extraction efficiency and enhance the purity of the product.

[0044] Preferably, the extraction further comprises washing the organic phase obtained after the extraction.

[0045] Preferably, the washing comprises washing the organic phase with water, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence.

[0046] Preferably, the solvent used for filtering and washing the silica gel pad includes any one of petroleum ether, dichloromethane, methanol, ethanol, tetrahydrofuran or ethyl acetate, or a combination of at least two thereof, preferably a combination of petroleum ether, dichloromethane and methanol.

[0047] Preferably, the silica gel pad filtration and washing comprises mixing and dissolving the extract concentrate and dichloromethane, mixing with silica gel, concentrating under reduced pressure to dryness to form a silica gel filter layer, and then performing two steps of reduced pressure filtration and washing.

[0048] Exemplarily, during filtration and washing, a combination of petroleum ether and dichloromethane or a single solvent of dichloromethane in a volume ratio of 1: (1 to 10) (for example, it can be 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, etc.) is first used for filtration and washing until the filtrate is colorless or nearly colorless, and trace impurities (including unreacted raw material cryptotanshinone and various small polar by-products) are removed, and then a combination of dichloromethane and methanol in a volume ratio of (500 to 1): 1 (for example, it can be 450: 1, 400: 1, 350: 1, 300: 1, 250: 1, 200: 1, 150: 1, 100: 1, 50: 1, 10: 1, 2: 1, etc.) or a single solvent of methanol or a single solvent of ethanol is used for filtration and washing until the filtrate is colorless or nearly colorless, and the second step filtrate is collected to obtain a pure solution of new cryptotanshinone.

[0049] Preferably, the amount of silica gel used in the silica gel pad filtration is 1 to 10 times the amount of the concentrate, for example, it can be 2 times, 4 times, 6 times, 8 times, etc., preferably 3 to 5 times.

[0050] Preferably, the particle size of the silica gel is 100-300 meshes, for example, 100 meshes, 150 meshes, 200 meshes, 250 meshes, 300 meshes, etc., preferably 200-300 meshes.

[0051] Preferably, the recrystallization comprises mixing and dissolving the filtrate concentrate and a good solvent, and adding a poor solvent for crystallization to obtain the neocryptotanshinone.

[0052] Preferably, the good solvent comprises dichloromethane.

[0053] Preferably, the poor solvent comprises petroleum ether.

[0054] In the present invention, the amount of good solvent added should be as small as possible, and should be added until the filtrate concentrate is just dissolved. The amount of good solvent to poor solvent is 1:(1-10), for example, it can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, etc.), preferably 1:(2-5).

[0055] In a specific embodiment, the elution procedure of the filtration and washing can be a two-step vacuum filtration and washing, that is, a combination of petroleum ether and dichloromethane with a volume ratio of 1:10 and a combination of dichloromethane and methanol with a volume ratio of 1:1 are used for filtration and washing, and the criterion for the end of filtration and washing is preferably that the filtrate is colorless or nearly colorless, and the latter filtrate is collected to obtain a pure solution of neocryptotanshinone; the recrystallization is to reduce the pressure and concentrate the obtained pure solution of neocryptotanshinone to dryness, then dissolve it with as little dichloromethane as possible, add petroleum ether (the ratio of dichloromethane to petroleum ether is 1:3) for shaking, and then let it stand to settle.

[0056] In a specific embodiment, the elution procedure of the filtration and washing can be a two-step vacuum filtration and washing, that is, using a single solvent methyl chloride, a single solvent methanol or a single solvent ethanol for filtration and washing in sequence, collecting the latter filtrate to obtain a pure solution of neocryptotanshinone; the recrystallization is to reduce the pressure and concentrate the obtained pure solution of neocryptotanshinone to dryness, then dissolve it with as little dichloromethane as possible, add petroleum ether (the ratio of dichloromethane to petroleum ether is 1:5) for shaking, and then let it stand to settle.

[0057] In the present invention, petroleum ether, dichloromethane and methanol three-system solvents are used for step-by-step reduced pressure filtering and washing during filtering and washing of the silica gel cushion layer, and dichloromethane and petroleum ether two-system solvents are used for shaking, standing for sedimentation and reduced pressure filtering to obtain the product during recrystallization, which is beneficial to improving the purification efficiency, enhancing the purity of the product, being convenient and fast, and being conducive to industrialization.

[0058] Preferably, the preparation method comprises the following steps:

[0059] (1) mixing cryptotanshinone, an alkaline reagent and an organic solvent, and reacting them at -20 to 40° C. for 1 to 24 hours to complete the ring-opening and rearrangement reactions of cryptotanshinone to obtain a new salt of cryptotanshinone;

[0060] (2) concentrating the system obtained in step (1) under reduced pressure, recovering the organic solvent, adding an acid reagent and water, reacting at -20 to 40° C. for 0.5 to 12 hours, completing the neutralization reaction, and obtaining neocryptanshinones;

[0061] The molar ratio of cryptotanshinone, the alkaline reagent and the acid reagent is 1:(1-20):(0.8-20).

[0062] Compared with the prior art, the present invention has at least the following beneficial effects:

[0063] The preparation method of the new cryptotanshinone provided by the present invention uses commercially available and relatively inexpensive cryptotanshinone as a starting material, obtains the target compound new cryptotanshinone through a two-step reaction (ring-opening reaction + rearrangement reaction) and a one-step one-pot reaction method, which not only simplifies the synthesis route, but also effectively improves the yield and purity of the product, wherein the yield of the crude product is greater than 80%, and can be as high as 85% or more within a preferred range, and the purity of the product after column chromatography purification is as high as 99%;

[0064] In addition, the preparation method is mature and stable, easy to operate, the reagents and solvents used are simple and easy to obtain, and asymmetric reagents and precious metals are avoided. The organic solvents used can be recycled and reused, which has good economic benefits, is environmentally friendly, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 This is the synthetic route of the new cryptotanshinone (Compound 3) in Example 1.

[0066] Figure 2 It is the new cryptotanshinone (compound 3) in Example 1 1 H NMR spectra.

[0067] Figure 3 It is the new cryptotanshinone (compound 3) in Example 1 13 C NMR spectrum.

[0068] Figure 4 This is the high-resolution ESI mass spectrum of the new cryptotanshinone (compound 3) in Example 1.

[0069] Figure 5 This is the HPLC chart of the new cryptotanshinone (Compound 3) in Example 1. DETAILED DESCRIPTION

[0070] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. However, the following examples are only simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0071] Example 1

[0072] This embodiment provides a method for preparing a new cryptotanshinone, the preparation method comprising the following steps:

[0073] (1) Add 4.14 g (73.8 mmol) of potassium hydroxide and 60 mL of anhydrous ethanol to a reaction flask, stir the mixture to dissolve, then dropwise add 80 mL of anhydrous ethanol solution of 10.5 g (35.4 mmol) of cryptotanshinone under ice bath cooling and steady stirring, remove the ice bath after the dropwise addition, and stir the reaction mixture at 25° C. for 5 h to obtain a salt of neocryptotanshinone; concentrate under reduced pressure to recover the ethanol solvent, add 80 mL of water to the residue to dissolve into a suspension, and then extract with dichloromethane (5×100 mL, the organic phase of the last extraction is nearly colorless), combine the dichloromethane solutions of the organic phases, and concentrate under reduced pressure to recover the dichloromethane solvent to obtain an aqueous solution of the salt of neocryptotanshinone;

[0074] (2) 80 mL of 1N dilute hydrochloric acid (80.0 mmol) was added to the aqueous solution under ice-bath cooling, and the ice-bath was removed after stirring. The mixture was stirred for 1 h at 25° C. The aqueous phase was extracted with a dichloromethane-methanol binary solvent system (specifically, dichloromethane, dichloromethane and methanol with a volume ratio of 10:1, dichloromethane and methanol with a volume ratio of 5:1, and dichloromethane and methanol with a volume ratio of 1:1 were extracted in sequence, 4×200 mL). The organic phases were combined and washed with water, saturated sodium bicarbonate aqueous solution, and saturated brine in sequence. The obtained organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to recover the organic solvent to obtain a brown solid. 10.1 g of solid (crude product yield 90.8%); the crude product was dissolved in dichloromethane and then mixed with 50 g of silica gel, concentrated under reduced pressure to dryness to form a silica gel cushion layer, and filtered and washed in two steps using a petroleum ether-dichloromethane-methanol ternary solvent system (specifically, eluted with petroleum ether and dichloromethane in a volume ratio of 1:10, and dichloromethane and methanol in a volume ratio of 1:1), the second step filtrate was collected and concentrated under reduced pressure to remove the organic solvent, and dichloromethane was added dropwise to the residue until it was just dissolved, and petroleum ether equivalent to 3 times the volume of dichloromethane used was added to shake, allowed to stand overnight to settle, and filtered to dryness to obtain 9.22 g of a dark orange-red solid, which is neocryptanthone (compound 3).

[0075] The structural characterization data are as follows:

[0076] 1 H NMR (500MHz, CDCl3, δppm): 7.99(d,J=7.0Hz,1H,ArH),7.97(br,1H,OH),7.76(d,J=6.5Hz,1H,Ar-H),3.83-3.95(m,2H,(CH3)CH CH2OH),3.43-3.46(m,1H,(CH3)CHCH2OH),3.26(t,J=5.5Hz,2H,CH2),1.83-1.85(m,2H,CH 2),1.67-1.69(m,2H,CH2),1.62(br,1H,OH),1.32(s,6H,CH3×2),1.29(d,J=6.0Hz,3H,( CH3 )CHCH2OH); 13 C NMR (125MHz, CDCl3, δppm): 185.4 (C=O), 182.9 (C=O), 154.0, 153.0, 141.0, 133.4, 132.6, 126.4, 125.2,122.9,65.6,37.7,34.8,33.1,33.0,31.8,29.9,19.1,14.6; HRMS(ESI):m / z313.1446[MH] - (calcd for C 19 H 21 O4,313.1445).

[0077] The synthetic route of the product is Figure 1 As shown; product 1 H NMR spectra, 13 C NMR, high-resolution ESI mass spectrometry, and HPLC Figure 2-Figure 5 shown.

[0078] Example 2

[0079] This embodiment provides a method for preparing a new cryptotanshinone, the preparation method comprising the following steps:

[0080] (1) Add 4.14 g (73.8 mmol) of potassium hydroxide and 60 mL of anhydrous ethanol to a reaction flask, stir the mixture to dissolve, then dropwise add 80 mL of anhydrous ethanol solution of 10.5 g (35.4 mmol) of cryptotanshinone under ice bath cooling and steady stirring, remove the ice bath after the dropwise addition, and stir the reaction mixture at 25° C. for 5 h to obtain a salt of neocryptotanshinone; concentrate under reduced pressure to recover the ethanol solvent, add 80 mL of water to the residue to dissolve into a suspension, and then extract with dichloromethane (5×100 mL, the organic phase of the last extraction is nearly colorless), combine the dichloromethane solutions of the organic phases, and concentrate under reduced pressure to recover the dichloromethane solvent to obtain an aqueous solution of the salt of neocryptotanshinone;

[0081] (2) 40 mL of 1N dilute sulfuric acid (80.0 mmol) was added to the aqueous solution under ice-bath cooling, and the ice-bath was removed after stirring. The mixture was stirred for 1 h at 25° C. The aqueous phase was extracted with a dichloromethane-methanol binary solvent system (specifically, dichloromethane, dichloromethane and methanol with a volume ratio of 10:1, dichloromethane and methanol with a volume ratio of 5:1, dichloromethane and methanol with a volume ratio of 3:1, and dichloromethane and methanol with a volume ratio of 1:1 were used for extraction, 5×200 mL). The organic phases were combined and washed with water and saturated brine in turn. The organic phases were dried with anhydrous sodium sulfate, and concentrated under reduced pressure to recover the organic solvent to obtain brown phase. 10.0 g of brown solid (crude product yield 89.9%); the crude product was dissolved in dichloromethane and then mixed with 50 g of silica gel, concentrated under reduced pressure to dryness to form a silica gel cushion layer, and filtered and washed in two steps using a petroleum ether-dichloromethane-methanol ternary solvent system (specifically, eluted with petroleum ether and dichloromethane in a volume ratio of 1:10, and dichloromethane and methanol in a volume ratio of 1:1), the second step filtrate was collected and concentrated under reduced pressure to remove the organic solvent, dichloromethane was added dropwise to the residue until it was just dissolved, petroleum ether equivalent to 3 times the volume of dichloromethane used was added to shake, allowed to stand overnight to settle, and filtered to dryness to obtain 9.12 g of a dark orange-red solid, which was neocryptanthone (compound 3).

[0082] The structural characterization data are as follows:

[0083] 1H NMR (500MHz, CDCl3, δppm): 7.99 (d, J=7.0Hz, 1H, ArH), 7.98 (br, 1H, OH), 7.76 (d ,J=6.5Hz,1H,Ar-H),3.83-3.95(m,2H,(CH3)CHCH2OH),3.43-3.46(m,1H,(CH3)C HCH2OH),3.26(t,J=5.5Hz,2H,CH2),1.83-1.85(m,2H,CH2),1.67-1.69(m,2H,C H2), 1.62 (br, 1H, OH), 1.32 (s, 6H, CH3×2), 1.29 (d, J = 6.0Hz, 3H, (CH3)CHCH2OH).

[0084] Example 3

[0085] This embodiment provides a method for preparing a new cryptotanshinone, the preparation method comprising the following steps:

[0086] (1) Add 4.14 g (73.8 mmol) of potassium hydroxide and 60 mL of anhydrous ethanol to a reaction flask, stir the mixture to dissolve, then dropwise add 80 mL of anhydrous ethanol solution of 10.5 g (35.4 mmol) of cryptotanshinone under ice bath cooling and steady stirring, remove the ice bath after the dropwise addition, and stir the reaction mixture at 25° C. for 5 h to obtain a salt of neocryptotanshinone; concentrate under reduced pressure to recover the ethanol solvent, add 80 mL of water to the residue to dissolve into a suspension, and then extract with dichloromethane (5×100 mL, the organic phase of the last extraction is nearly colorless), combine the dichloromethane solutions of the organic phases, and concentrate under reduced pressure to recover the dichloromethane solvent to obtain an aqueous solution of the salt of neocryptotanshinone;

[0087] (2) 4.3 mL of glacial acetic acid (75.2 mmol) + 50 mL of water were added to the aqueous solution under ice bath cooling, stirred well and then the ice bath was removed. The mixture was stirred at 25° C. for 2 h. The aqueous phase was extracted with a dichloromethane-methanol binary solvent system (specifically, dichloromethane, dichloromethane and methanol with a volume ratio of 10:1, and dichloromethane and methanol with a volume ratio of 1:1 were used in sequence, 3×600 mL). The organic phases were combined and washed with water and saturated brine in sequence. The obtained organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure to recover the organic solvent, and 9.6 g of a brown solid was obtained (the yield of the crude product was 8. 6.3%); the crude product was dissolved in dichloromethane and then mixed with 50 g of silica gel, concentrated under reduced pressure to dryness to form a silica gel cushion layer, and filtered and washed in two steps using a petroleum ether-dichloromethane-methanol ternary solvent system (specifically, eluted with petroleum ether and dichloromethane in a volume ratio of 1:10 and dichloromethane and methanol in a volume ratio of 1:1), the filtrate from the second step was collected and concentrated under reduced pressure to remove the organic solvent, dichloromethane was added dropwise to the residue until it was just dissolved, petroleum ether equivalent to 3 times the volume of dichloromethane used was added, shaken, allowed to stand overnight for sedimentation, and filtered to dryness to obtain 9.02 g of a dark orange-red solid, which was neocryptanthone (compound 3).

[0088] The structural characterization data are as follows:

[0089] 1H NMR (500MHz, CDCl3, δppm): 7.99 (d, J=7.0Hz, 1H, ArH), 7.98 (br, 1H, OH), 7.75 (d ,J=6.5Hz,1H,Ar-H),3.83-3.95(m,2H,(CH3)CHCH2OH),3.43-3.46(m,1H,(CH3)C HCH2OH),3.26(t,J=5.5Hz,2H,CH2),1.83-1.85(m,2H,CH2),1.67-1.69(m,2H,C H2), 1.62 (br, 1H, OH), 1.32 (s, 6H, CH3×2), 1.29 (d, J = 6.0Hz, 3H, (CH3)CHCH2OH).

[0090] Example 4

[0091] This embodiment provides a method for preparing a new cryptotanshinone, the preparation method comprising the following steps:

[0092] (1) 0.29 g (7.25 mmol) of sodium hydroxide and 6 mL of anhydrous ethanol were added to a reaction flask, and the mixture was stirred to dissolve. Subsequently, 8 mL of anhydrous ethanol solution of 1.05 g (3.54 mmol) of cryptotanshinone was added dropwise under ice bath cooling and steady stirring. After the addition was complete, the ice bath was removed, and the reaction mixture was stirred at 25° C. for 5 h to obtain a salt of a new cryptotanshinone; the ethanol solvent was recovered by concentrating under reduced pressure, and the residue was dissolved in 80 mL of water to form a suspension, and then extracted with dichloromethane (5×100 mL, the organic phase of the last extraction was nearly colorless), and the organic phase dichloromethane solutions were combined, and the dichloromethane solvent was recovered by concentrating under reduced pressure to obtain an aqueous solution of a salt of a new cryptotanshinone;

[0093] (2) 8.0 mL of 1N dilute hydrochloric acid (8.0 mmol) was added to the aqueous solution under ice-bath cooling, stirred and then the ice-bath was removed. Stirring was continued at 25° C. for 1 h. The aqueous phase was extracted with a dichloromethane-methanol binary solvent system (specifically, dichloromethane, dichloromethane and methanol with a volume ratio of 20:1, dichloromethane and methanol with a volume ratio of 5:1, and dichloromethane and methanol with a volume ratio of 1:1 were extracted in sequence, 4×600 mL). The organic phases were combined and washed with water and saturated brine in sequence. The obtained organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to recover the organic solvent to obtain a brown solid 0.9 8g (crude product yield 88.1%); the crude product was dissolved in dichloromethane and then mixed with 50g of silica gel, concentrated under reduced pressure to dryness to form a silica gel cushion layer, and filtered and washed in two steps using a petroleum ether-dichloromethane-methanol ternary solvent system (specifically, eluted with petroleum ether and dichloromethane in a volume ratio of 1:10, and dichloromethane and methanol in a volume ratio of 1:1), the second step filtrate was collected and concentrated under reduced pressure to remove the organic solvent, dichloromethane was added dropwise to the residue until it was just dissolved, petroleum ether equivalent to 3 times the volume of dichloromethane used was added, shaken, allowed to stand overnight to settle, and filtered to dryness to obtain 0.89g of a dark orange-red solid, which is neocryptanthone (compound 3).

[0094] The structural characterization data are as follows:

[0095] 1H NMR (500MHz, CDCl3, δppm): 7.99 (d, J=7.0Hz, 1H, ArH), 7.96 (br, 1H, OH), 7.76 (d ,J=6.5Hz,1H,Ar-H),3.83-3.95(m,2H,(CH3)CHCH2OH),3.43-3.46(m,1H,(CH3)C HCH2OH),3.26(t,J=5.5Hz,2H,CH2),1.83-1.85(m,2H,CH2),1.67-1.69(m,2H,C H2), 1.62 (br, 1H, OH), 1.32 (s, 6H, CH3×2), 1.29 (d, J = 6.0Hz, 3H, (CH3)CHCH2OH).

[0096] Example 5

[0097] This embodiment provides a method for preparing a new cryptotanshinone, which differs from Embodiment 1 only in that the two-step filtration and washing in step (2) are performed by eluting with petroleum ether and dichloromethane in a volume ratio of 1:8 and dichloromethane and methanol in a volume ratio of 10:1, respectively.

[0098] Example 6

[0099] This embodiment provides a method for preparing a new cryptotanshinone, which differs from Embodiment 1 only in that the two-step filtration and washing in step (2) are eluted with petroleum ether and dichloromethane in a volume ratio of 1:5 and dichloromethane and methanol in a volume ratio of 100:1, respectively.

[0100] Example 7

[0101] This embodiment provides a method for preparing a new cryptotanshinone, which is different from Embodiment 1 only in that the alkaline reagent is sodium methoxide.

[0102] Example 8

[0103] This embodiment provides a method for preparing a new cryptotanshinone, which is different from Embodiment 1 only in that the alkaline reagent is sodium ethoxide.

[0104] Example 9

[0105] This embodiment provides a method for preparing a new cryptotanshinone, which is different from Example 1 only in that the amount of potassium hydroxide used is 35.4 mmol, and the amount of dilute hydrochloric acid used is 41.0 mmol.

[0106] Example 10

[0107] This embodiment provides a method for preparing a new cryptotanshinone, which is different from Example 1 only in that the amount of potassium hydroxide used is 177 mmol, and the amount of dilute hydrochloric acid used is 205.0 mmol.

[0108] Embodiment 11

[0109] This embodiment provides a method for preparing a new cryptotanshinone, which differs from Embodiment 1 only in that, in step (2), dichloromethane is replaced by ethyl acetate during extraction, and other operations are similar to those of Embodiment 1.

[0110] Example 12

[0111] This embodiment provides a method for preparing a new cryptotanshinone, which differs from Embodiment 1 only in that, in step (2), dichloromethane is replaced by ethyl acetate during filtration and washing of the silica gel pad, and other operations are similar to those of Embodiment 1.

[0112] Example 13

[0113] This embodiment provides a method for preparing a new cryptotanshinone, which differs from Embodiment 1 only in that, in step (2), the petroleum ether-dichloromethane-methanol ternary solvent system is replaced with a dichloromethane-methanol binary solvent system when filtering and washing the silica gel pad (i.e., first filtering and washing with dichloromethane until the eluent is nearly colorless, and then filtering and washing with methanol until the eluent is nearly colorless). The other operations refer to Embodiment 1.

[0114] The pure product yield and product purity of the new cryptotanshinone prepared by the preparation method provided in Examples 1-13 are shown in Table 1.

[0115] Table 1

[0116]

[0117]

[0118] The test results show that:

[0119] (1) It can be seen from Examples 1 to 13 that the present invention uses cryptotanshinone as the starting material, and obtains the target compound neocrypttanshinone through a two-step reaction (ring-opening reaction + rearrangement reaction) and a one-step one-pot reaction method, which simplifies the synthesis and purification steps, makes the reaction conditions easy to control and reduces the production cost, while improving the yield and purity of the product.

[0120] (2) By comparing Example 1 with Examples 9-10, it can be seen that the present invention can further accelerate the reaction process and improve the yield and purity of the product by further limiting the amount of the alkaline reagent; by comparing Example 1 with Examples 11-13, it can be seen that the present invention has a more excellent separation and purification effect under a specific compounded solvent by further compounding the extraction and silica gel pad filtration solvents.

[0121] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing a new cryptotanshinone, characterized in that: The preparation method comprises the following steps: (1) Cryptotanshinone undergoes ring opening and rearrangement reaction under the action of an alkaline reagent to generate a new cryptotanshinone salt; (2) The salt of neocryptotanshinone undergoes a neutralization reaction under the action of an acid reagent to obtain neocryptotanshinone.

2. The preparation method according to claim 1, characterized in that: The alkaline agent includes any one of potassium hydroxide, sodium hydroxide, sodium methoxide or sodium ethoxide, or a combination of at least two thereof.

3. The preparation method according to claim 1 or 2, characterized in that: The acid reagent includes any one of hydrochloric acid, sulfuric acid or glacial acetic acid, or a combination of at least two of them.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The molar ratio of cryptotanshinone, the alkaline reagent and the acid reagent is 1:(1-20):(0.8-20), preferably 1:(2-3):(2-3).

5. The preparation method according to any one of claims 1 to 4, characterized in that: In step (1), the reaction is carried out in an organic solvent; Preferably, the organic solvent comprises any one of ethanol, methanol or propanol or a combination of at least two thereof; Preferably, after the reaction, the steps of reducing pressure and concentrating to recover the organic solvent, adding water to dissolve, extracting with an organic solvent, and concentrating under reduced pressure and concentrating to recover the organic solvent are also included; Preferably, the organic solvent used for the extraction includes any one of dichloromethane, ethyl acetate or tetrahydrofuran or a combination of at least two thereof, and dichloromethane is further preferred; Preferably, in step (1), the reaction temperature is -20 to 40°C, and the reaction time is 1 to 24 hours; Further preferably, in step (1), the reaction temperature is 0 to 30° C., and the reaction time is 1 to 6 hours.

6. The preparation method according to any one of claims 1 to 5, characterized in that: In step (2), the reaction is carried out in an aqueous solution; Preferably, in step (2), the reaction temperature is -20 to 40°C, and the reaction time is 0.5 to 12 hours; More preferably, in step (2), the reaction temperature is 10 to 30° C., and the reaction time is 0.5 to 3 h.

7. The preparation method according to any one of claims 1 to 6, characterized in that: In step (2), the reaction further includes a post-treatment process; Preferably, the post-treatment process includes: extracting the reaction solution, concentrating the extract, filtering and washing with a silica gel pad, concentrating the filtrate and recrystallizing to obtain the neocrypttanshinone.

8. The preparation method according to claim 7, characterized in that: The solvent used for the extraction includes any one of ethyl acetate, dichloromethane, tetrahydrofuran or methanol or a combination of at least two thereof, preferably a combination of dichloromethane and methanol; Preferably, the extraction further comprises washing the organic phase obtained after the extraction; Preferably, the washing comprises washing the organic phase with water, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence.

9. The preparation method according to claim 7 or 8, characterized in that: The solvent used for filtering and washing the silica gel pad includes any one of petroleum ether, dichloromethane, methanol, ethanol, tetrahydrofuran or ethyl acetate, or a combination of at least two thereof, preferably a combination of petroleum ether, dichloromethane and methanol; Preferably, the amount of silica gel used in the silica gel pad filtration is 1 to 10 times the amount of the concentrate, preferably 3 to 5 times; Preferably, the particle size of the silica gel is 100 to 300 mesh, preferably 200 to 300 mesh; Preferably, the recrystallization comprises mixing and dissolving the filtrate concentrate and a good solvent, and adding a poor solvent for crystallization to obtain the neocryptotanshinone; Preferably, the good solvent comprises dichloromethane; Preferably, the poor solvent comprises petroleum ether.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: (1) mixing cryptotanshinone, an alkali reagent and an organic solvent, reacting at -20 to 40° C. for 1 to 24 hours to complete the ring-opening and rearrangement reactions of cryptotanshinone, concentrating the reaction system under reduced pressure to recover the organic solvent, adding water to dissolve, extracting with an organic solvent and concentrating under reduced pressure again to recover the organic solvent, thereby obtaining an aqueous solution of a salt of new cryptotanshinone; (2) adding an acid reagent to the aqueous solution obtained in step (1), reacting at -20 to 40° C. for 0.5 to 12 hours to complete a neutralization reaction and obtain neocryptotanshinone; The molar ratio of cryptotanshinone, the alkaline reagent and the acid reagent is 1:(1-20):(0.8-20).

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