A dehydrated icariin intermediate compound

Abstract

The present invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a dehydrated icariin intermediate compound. The present invention uses 2-(benzyloxy)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl) ethyl-1-ketone as a starting material, and reacts with 1-bromo-3-methylbutyl-2-ene under the action of a catalyst to obtain a new dehydrated icariin intermediate 2-(benzyloxy)-1-(2,4-bis(benzyloxy)-6-((3-methylbutyl-2-ene-1-yl)oxy)phenyl) ethyl-1-ketone. At the same time, the present invention provides a method for preparing dehydrated icariin by using the new intermediate compound: 2-(benzyloxy)-1-(2,4-bis(benzyloxy)-6-((3-methylbutyl-2-ene-1-yl)oxy)phenyl) ethyl-1-ketone undergoes a rearrangement reaction and then reacts with 4-methoxybenzoyl chloride, and the obtained product is cyclized and then debenzylated to obtain dehydrated icariin. The novel intermediate synthesis method provided by the present invention is simple. The intermediate introduces a protective group, introduces an isopentenyl group before forming a flavonoid skeleton, and finally removes the protective group in one step to obtain dehydrated icariin. The synthetic route is short, the yield is high, the reaction conditions are mild, the process is stable, and it is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a dehydrated icariin intermediate compound. Background Art

[0002] Icariin, chemical name: 3,5,7-trihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-ene) chalcone, molecular formula: C 21 H 20 O6; molecular weight: 368.13; CAS number: 118525-40-9, the structural formula is as follows:

[0003]

[0004] Dehydrated icariin belongs to the flavonol class of compounds, which is widely found in plants. It is numerous, has complex and diverse structures, and has many important biological activities and pharmacological effects, such as anti-tumor, anti-cancer cell proliferation, anti-osteoporosis, estrogen regulation, and nervous system regulation. At present, icariin is mainly obtained by extracting it from plants, but the natural content is low, and the separation and purification is relatively complicated, which limits its development in the medical field. The total synthesis of a single compound of dehydrated icariin solves this problem, which provides a guarantee for our next planned clinical trials and possible drug use.

[0005] There are few reports on the total synthesis of icariin in the prior art. Chinese patent application CN200610165354.7 discloses a method for synthesizing icariin. This route uses kaempferol-4-oxymethyl ether as a starting material to prepare icariin. The synthesis steps described in the patent are as follows:

[0006]

[0007] However, in the above method, the synthesis of kaempferol-4-oxymethyl ether requires eight steps of reaction, which is complicated to operate. The Claisen rearrangement requires microwave heating, which has high production cost and is not conducive to large-scale industrial production.

[0008] In the March 2013 issue of Organic Chemistry, an article entitled "Synthesis of Icariin" was published. The article mentioned that in the rearrangement process from compound (3) to compound (4), tris(6,6,7,7,8,8,8,-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium was used as a catalyst, and the yield was 42%. The above catalyst is expensive and the reaction yield is low, which is not conducive to industrial production. How to optimize or avoid Claisen rearrangement becomes the key to this synthetic route.

[0009] Chinese patent application CN201910220551.1 reports that the isopentenyl group is first connected to the 8-carbon by ortho-rearrangement, and then a series of reactions for forming the flavonoid skeleton are performed to obtain dehydrated icariin. The synthesis steps described in the patent are as follows:

[0010]

[0011] Although the reaction conditions of this route are relatively mild, the synthetic route is long, and the introduction and removal of protective groups are difficult, which is not conducive to purification and industrial production. Summary of the invention

[0012] At present, there are many difficulties in the synthesis of epimedium compounds, such as difficulty in introducing isopentenyl, difficulty in removing protective groups, complex process, expensive catalysts, many by-products, etc. The present invention provides a new dehydrated epimedium intermediate compound and a preparation method, which introduces isopentenyl before forming a flavonoid skeleton and uses an easily removable benzyl as a protective group. The synthesis of dehydrated epimedium using the intermediate has a short route, high yield, mild reaction conditions, stable process, and is suitable for large-scale industrial production.

[0013] The present invention is specifically implemented through the following technical solutions:

[0014] The first aspect of the present invention provides a new dehydrated icariin intermediate compound, the structure of which is shown in Formula IV:

[0015]

[0016] The second aspect of the present invention provides a method for preparing compound IV, comprising the following steps:

[0017] Compound II, compound III, a base and organic solvent A are added to a reaction bottle, stirred to dissolve, and reacted by stirring at controlled temperature. After the reaction is complete, compound IV is obtained. The synthesis route is as follows:

[0018]

[0019] Preferably, the base is selected from cesium carbonate, potassium hydroxide, sodium hydroxide, potassium carbonate, and potassium tert-butoxide, among which cesium carbonate is particularly preferred.

[0020] Preferably, the molar ratio of compound II, compound III and base is 1:1.0-1.8:1.0-2.0, among which 1:1.2:1.1 is particularly preferred.

[0021] Preferably, the organic solvent A is selected from one of tetrahydrofuran, acetone, acetonitrile, toluene, xylene or a combination thereof.

[0022] Preferably, the reaction temperature is 50-100°C, with 80°C-85°C being particularly preferred.

[0023] In a preferred embodiment, after the reaction is completed, a post-treatment operation is required, specifically: purified water and an extractant are added to the reaction solution, the liquids are separated, the organic phase is collected, the organic phase is dried over anhydrous sodium sulfate, the desiccant is removed by filtration, and the compound IV is obtained by concentrating under reduced pressure; the extractant is one of ethyl acetate, dichloromethane, and chloroform, or a combination thereof.

[0024] The third aspect of the present invention provides a use of compound IV for preparing dehydrated icariin.

[0025] The method for preparing dehydrated icariin using compound IV comprises the following scheme: intermediate IV is reacted with a catalyst to obtain intermediate V; intermediate V and compound VI are reacted with an alkali to obtain compound VII; compound VII undergoes a cyclization reaction under alkaline conditions to obtain intermediate VIII; intermediate VIII undergoes a reduction reaction to remove the benzyl group to obtain dehydrated icariin, and the synthesis route is as follows:

[0026]

[0027] Preferably, the above steps are further described in detail in the following sections:

[0028] Preparation of Compound V

[0029] The preparation method of compound V is as follows: adding compound IV, a catalyst and an organic solvent B into a reaction bottle, stirring at room temperature until the reaction is completed, and post-processing the reaction to obtain compound V;

[0030] Preferably, the catalyst is selected from one of bismuth trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, scandium trifluoromethanesulfonate and europium trifluoromethanesulfonate, among which bismuth trifluoromethanesulfonate is particularly preferred.

[0031] Preferably, the molar ratio of compound IV to catalyst is 1:0.05-0.2, with 1:0.1 being particularly preferred.

[0032] Preferably, the organic solvent is one of tetrahydrofuran, acetonitrile, acetone, toluene, dichloromethane or a combination thereof.

[0033] In a preferred embodiment, after the reaction is completed, a post-treatment operation is required, specifically: the reaction solution is added to purified water, an extractant is added, the organic phase is collected, the organic phase is dried over anhydrous sodium sulfate, the desiccant is filtered out, and the intermediate V is concentrated under reduced pressure; the extractant is one of ethyl acetate, dichloromethane, and chloroform, or a combination thereof.

[0034] Preparation of Compound VII

[0035] Add compound V, compound VI, a base and an organic solvent into a reaction flask, and heat under reflux until the reaction is complete to obtain an intermediate compound VII;

[0036] Preferably, the base is selected from one of triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and sodium methoxide, among which triethylamine is particularly preferred.

[0037] Preferably, the molar ratio of compound V, compound VI and base is 1:1.0-2.0:1.0-2.0, among which 1:1.3:1.5 is particularly preferred.

[0038] Preferably, the organic solvent C is selected from one of acetone, tetrahydrofuran, acetonitrile, dichloromethane, cyclohexane or a combination thereof.

[0039] In a preferred embodiment, after the reaction is completed, a post-treatment operation is required, specifically: the reaction solution is cooled to room temperature, purified water and an extractant are added, the organic phase is collected, the organic phase is dried over anhydrous sodium sulfate, the desiccant is removed by filtration, and the solid obtained after reduced pressure concentration is added to ethanol for recrystallization to obtain compound VII; the extractant is one of ethyl acetate, dichloromethane, and chloroform, or a combination thereof.

[0040] Preparation of Compound VIII

[0041] Add compound VII, a base and an organic solvent D into a reaction bottle, heat and stir, and stop heating after the reaction is complete to obtain compound VIII;

[0042] Preferably, the base is selected from potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, and potassium tert-butoxide, among which potassium hydroxide is particularly preferred.

[0043] Preferably, the molar ratio of compound VII to base is 1:1.0-2.0, with 1:1.5 being particularly preferred.

[0044] Preferably, the solvent D is selected from pyridine, N,N-diethylaniline, N-methylpyrrolidone or a combination thereof.

[0045] Preferably, the reaction temperature is 60°C to 110°C, particularly preferably 80°C to 85°C.

[0046] In a preferred embodiment, after the reaction is completed, post-treatment operations are required, specifically: the reaction solution is cooled to room temperature, an extractant is added, the organic phase is collected, the organic phase is concentrated under reduced pressure, and then recrystallized from ethyl acetate / n-hexane (volume ratio 1:3) to obtain compound VIII; the extractant is one of ethyl acetate, dichloromethane, chloroform or a combination thereof.

[0047] Preparation of Dehydrated Icariin

[0048] Compound VIII, a catalyst and an organic solvent E are added to a reaction bottle, hydrogen is introduced into the bottle, and the reaction is stirred under temperature control. Stirring is stopped after the reaction is detected to be complete, thereby obtaining dehydrated icariin.

[0049] Preferably, the catalyst is selected from palladium carbon, palladium hydroxide, and palladium acetate, among which palladium carbon is particularly preferred.

[0050] Preferably, the molar ratio of compound VIII to catalyst is 1:0.05 to 0.2, with 1:0.10 being particularly preferred.

[0051] Preferably, the organic solvent E is selected from one of methanol, ethanol, acetone, tetrahydrofuran, acetonitrile, dichloromethane, 1,4-dioxane or a combination thereof.

[0052] Preferably, the reaction temperature is 20°C to 60°C

[0053] In a preferred embodiment, after the reaction is completed, a post-treatment operation is required, specifically: the reaction liquid is filtered, the organic phase is collected, purified water and an extractant are added to the organic phase, the organic phase is collected and dried with anhydrous sodium sulfate, the organic phase is concentrated under reduced pressure, and the obtained solid is recrystallized with methanol to obtain dehydrated icariin; the extractant is one of ethyl acetate, dichloromethane, chloroform or a combination thereof.

[0054] Beneficial effects achieved by the present invention:

[0055] 1. The present invention provides a new dehydrated icariin intermediate compound and a preparation method thereof. The reaction route for preparing dehydrated icariin using the new intermediate is short and the yield is high.

[0056] 2. The preparation method of dehydrated icariin provided by the present invention introduces an isopentenyl group before forming the flavonoid skeleton to improve the selectivity of the isopentenyl group; compound VII undergoes a cyclization reaction under alkaline conditions to obtain intermediate VIII, avoiding the complex operations required by the prior art such as the directing group and the pre-activation of the reaction site. DETAILED DESCRIPTION

[0057] The present invention is further described below by way of examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention, so simple improvements to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0058] The structure of the compound obtained by the present invention is confirmed:

[0059]

[0060] High resolution mass spectrum of compound IV: ESI-HRMS: m / z=523.6212 [M+H] + , 1 H-NMR (400MHz, CDCl3): δ7.30-7.46(m,15H),6.21-6.32(m,2H),5.39(t,J=6.8Hz,1H ),5.14-5.12(m,4H),4.82(d,J=3.6Hz,2H),4.68-4.62(m,4H),1.82(t,J=3.2Hz,2H); 13 C-NMR (400MHz, CDCl3) δ198.1,163.2,137.3,136.7,128.1,127.5,100.8,93.6,79.7,95.4,70.2,64.0,24.1,18.2.

[0061]

[0062] High resolution mass spectrum of compound V: ESI-HRMS: m / z = 523.2402 [M+H] + , 1 H-NMR (400MHz, CDCl3): δ12.12(s,1H),7.32-7.11(m,15H),6.24(s,1H),5.61(t,J=6.8Hz,1H ),5.16(s,4H),4.81(d,J=6.2Hz,2H),4.61(s,2H),3.33(d,J=4.8Hz,2H),1.82-1.73(m,6H); 13 C-NMR (100MHz, CDCl3) δ165.1,162.2,137.2,131.2,128.9,127.1,123.2,70.2,24.6,21.9,18.6.

[0063]

[0064] High resolution mass spectrum of compound VII: ESI-HRMS: m / z=657.2772 [M+H] + , 1H-NMR (400MHz, CDCl3): δ8.12-8.09(m,2H),7.30-7.50(m,15H),8.89-8.83(m,2H),8.58(s,1H),5.72(t,J=6 .8Hz,1H),5.18-5.16(m,4H),4.80-4.76(m,4H),3.83(t,J=4.8Hz,3H),3.33-3.29(m,2H);1.82-1.73(m,6H); 13 C-NMR (100MHz, CDCl3) δ198.1,165.2,159.2,157.2,138.9,131.1,123.2,128.2,122.6,113.2,104.2,97.3,79.2,71.3,57.2,21.5.

[0065]

[0066] High resolution mass spectrum of compound VIII: ESI-HRMS: m / z=639.6213 [M+H] + , 1 H-NMR (400MHz, CDCl3): δ7.52-7.29(m,17H),6.82-6.71(m,2H),6.32(s,1H),5.72(t ,J=6.8Hz,1H),5.22-4.96(m,6H),3.81(s,3H),3.34-3.12(m,2H),1.82-1.71(m,6H); 13 C-NMR (100MHz, CDCl3) δ175.1,168.2,159.2,157.2,138.9,132.1,129.1,122.1,115.2,110.2,95.2,72.1,53.2,22.3,11.3.

[0067]

[0068] High resolution mass spectrum of compound I: ESI-HRMS: m / z=368.1263[M+H] + , 1 H-NMR (400MHz, CDCl3): δ12.36(s,1H),10.86(s,1H),9.49(s,1H,),8.14(d,J=9.0Hz,2H),7.13(d,J =9.1Hz),6.30(s,1H),5.18(t,J=6.8Hz),3.85(s,3H,),3.44(d,J=6.7Hz),1.76(s,3H),1.53(s,3H);13 C-NMR (100MHz, CDCl3): δ176.6,161.4,160.7,158.5,153.9,146.5,136.4,13 1.5,129.6,124.1,122.9,114.6,106.1,103.6,98.3,55.9,25.3,21.8,18.4.

[0069] Preparation of Compound IV

[0070] Example 1

[0071] Add intermediate II (142.00 g, 0.31 mol), compound III (55.14 g, 0.37 mol), cesium carbonate (110.78 g, 0.34 mol) and 1000 mL of toluene into a three-necked flask, stir to dissolve, react at 80°C to 85°C for 6 hours, slowly cool the reaction solution to room temperature, add 600 mL of purified water and 500 mL of ethyl acetate, shake vigorously and let stand, collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure to obtain compound IV as a white solid powder with a yield of 90.1% and an HPLC purity of 99.78%.

[0072] Example 2

[0073] To a three-necked flask, intermediate II (142.00 g, 0.31 mol), compound III (46.20 g, 0.31 mol), potassium hydroxide (19.08 g, 0.34 mol) and 500 mL of toluene were added, stirred to dissolve, and reacted at 50°C to 55°C for 6 hours. The reaction solution was slowly cooled to room temperature, 400 mL of purified water and 300 mL of ethyl acetate were added, and the mixture was allowed to stand after vigorous shaking. The organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain compound IV as a white solid powder with a yield of 87.3% and an HPLC purity of 99.36%.

[0074] Example 3

[0075] To a three-necked flask, intermediate II (142.00 g, 0.31 mol), compound III (83.46 g, 0.56 mol), potassium carbonate (46.99 g, 0.34 mol) and 500 mL of p-xylene were added, stirred to dissolve, and reacted at 95°C-100°C for 6 hours. The reaction solution was slowly cooled to room temperature, 400 mL of purified water and 400 mL of ethyl acetate were added, and the mixture was allowed to stand after vigorous shaking. The organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain compound IV as a white solid powder with a yield of 86.9% and an HPLC purity of 99.28%.

[0076] Example 4

[0077] Add intermediate II (142.00 g, 0.31 mol), compound III (92.40 g, 0.62 mol), potassium tert-butoxide (76.30 g, 0.68 mol) and 500 mL of toluene into a three-necked flask, stir to dissolve, react at 100°C to 105°C for 4 hours, slowly cool the reaction solution to room temperature, add 500 mL of purified water and 600 mL of ethyl acetate, shake vigorously and let stand, collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure to obtain compound IV as a white solid powder with a yield of 81.5% and an HPLC purity of 98.82%.

[0078] Example 5

[0079] Add intermediate II (142.00 g, 0.31 mol), compound III (55.14 g, 0.37 mol), cesium carbonate (101.0 g, 0.31 mol) and 1000 mL of tetrahydrofuran into a three-necked flask, stir to dissolve, react at 55°C to 60°C for 6 hours, slowly cool the reaction solution to room temperature, add 600 mL of purified water and 500 mL of dichloromethane, shake vigorously and let stand, collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure to obtain compound IV as a white solid powder with a yield of 88.7% and an HPLC purity of 99.53%.

[0080] Example 6

[0081] Add intermediate II (142.00 g, 0.31 mol), compound III (55.14 g, 0.37 mol), cesium carbonate (202.0 g, 0.62 mol) and 1200 mL of acetonitrile into a three-necked flask, stir to dissolve, react at 75°C to 80°C for 6 hours, slowly cool the reaction solution to room temperature, add 600 mL of purified water and 600 mL of chloroform, shake vigorously and let stand, collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure to obtain compound IV as a white solid powder with a yield of 86.9% and an HPLC purity of 99.38%.

[0082] Example 7

[0083] Add intermediate II (142.00 g, 0.31 mol), compound III (55.14 g, 0.37 mol), cesium carbonate (221.56 g, 0.68 mol) and 1300 mL of acetone into a three-necked flask, stir to dissolve, react at 45°C to 50°C for 6 hours, slowly cool the reaction solution to room temperature, add 600 mL of purified water and 600 mL of chloroform, shake vigorously and let stand, collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure to obtain compound IV as a white solid powder with a yield of 82.3% and an HPLC purity of 98.64%.

[0084] Preparation of Compound V

[0085] Example 8

[0086] Compound IV (132.21 g, 0.25 mol), bismuth trifluoromethanesulfonate (16.40 g, 0.025 mol) and 500 mL of dichloromethane were added to a three-necked flask and stirred at room temperature until the reaction was completed. 500 mL of purified water and 500 mL of ethyl acetate were added thereto. The mixture was shaken vigorously and allowed to stand. The organic phase was collected and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure to obtain a yellow solid compound V with a yield of 88.3% and an HPLC purity of 99.61%.

[0087] Example 8

[0088] Compound IV (132.21 g, 0.25 mol), bismuth trifluoromethanesulfonate (8.20 g, 0.0125 mol) and 400 mL of tetrahydrofuran were added to a three-necked flask and stirred at room temperature until the reaction was completed. 300 mL of purified water and 300 mL of dichloromethane were added thereto. The mixture was shaken vigorously and allowed to stand. The organic phase was collected and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure to obtain a yellow solid compound V with a yield of 84.6% and an HPLC purity of 99.38%.

[0089] Example 9

[0090] Compound IV (132.21 g, 0.25 mol), ytterbium trifluoromethanesulfonate (31.01 g, 0.05 mol) and 500 mL of acetonitrile were added to a three-necked flask and stirred at room temperature until the reaction was completed. 500 ml of purified water and 500 mL of dichloromethane were added thereto. The mixture was shaken vigorously and allowed to stand. The organic phase was collected and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure to obtain a yellow solid compound V with a yield of 85.2% and an HPLC purity of 99.32%.

[0091] Example 10

[0092] Compound IV (132.21 g, 0.25 mol), scandium trifluoromethanesulfonate (3.69 g, 0.0075 mol) and 300 mL of acetone were added to a three-necked flask and stirred at room temperature until the reaction was completed. 300 mL of purified water and 300 mL of chloroform were added thereto. The mixture was shaken vigorously and allowed to stand. The organic phase was collected and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure to obtain a yellow solid compound V with a yield of 79.8% and an HPLC purity of 98.95%.

[0093] Embodiment 11

[0094] Compound IV (132.21 g, 0.25 mol), europium trifluoromethanesulfonate (32.95 g, 0.055 mol) and 500 mL of acetone were added to a three-necked flask and stirred at room temperature until the reaction was completed. 400 mL of purified water and 400 mL of chloroform were added thereto. The mixture was shaken vigorously and allowed to stand. The organic phase was collected and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and concentrated under reduced pressure to obtain a yellow solid compound V with a yield of 80.2% and an HPLC purity of 98.99%.

[0095] Preparation of Compound VII

[0096] Example 12

[0097] Add intermediate V (88.85 g, 0.17 mol), compound VI (37.53 g, 0.22 mol), triethylamine (26.31 g, 0.26 mol) and 500 mL of tetrahydrofuran to a three-necked flask, stir to dissolve, reflux for 5 hours, stop heating, and slowly cool to room temperature. Add 500 mL of ethyl acetate and 500 ml of purified water, shake vigorously and let stand, collect the organic phase, dry with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure. The obtained solid is recrystallized from 300 ml of anhydrous ethanol to obtain yellow solid compound VII, with a yield of 92.1% and a HPLC purity of 99.96%.

[0098] Example 13

[0099] Add intermediate V (88.85 g, 0.17 mol), compound VI (29.0 g, 0.17 mol), potassium hydroxide (14.59 g, 0.26 mol) and 500 mL of tetrahydrofuran to a three-necked flask, stir to dissolve, reflux for 5 hours, stop heating, and slowly cool to room temperature. Add 500 mL of ethyl acetate and 500 ml of purified water, shake vigorously and let stand, collect the organic phase, dry with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure. The obtained solid is recrystallized from 300 ml of anhydrous ethanol to obtain yellow solid compound VII, with a yield of 88.6% and a HPLC purity of 99.71%.

[0100] Embodiment 14

[0101] Add intermediate V (88.85 g, 0.17 mol), compound VI (58.0 g, 0.34 mol), potassium carbonate (35.93 g, 0.26 mol) and 500 mL of tetrahydrofuran to a three-necked flask, stir to dissolve, reflux for 5 hours, stop heating, and slowly cool to room temperature. Add 500 mL of ethyl acetate and 500 ml of purified water, shake vigorously and let stand, collect the organic phase, dry with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure. The obtained solid is recrystallized from 300 ml of anhydrous ethanol to obtain yellow solid compound VII, with a yield of 89.2% and a HPLC purity of 99.58%.

[0102] Embodiment 15

[0103] Add intermediate V (88.85 g, 0.17 mol), compound VI (64.82 g, 0.38 mol), potassium tert-butoxide (42.64 g, 0.38 mol) and 500 mL of tetrahydrofuran to a three-necked flask, stir to dissolve, reflux for 5 hours, stop heating, and slowly cool to room temperature. Add 500 mL of dichloromethane and 500 ml of purified water, shake vigorously and let stand, collect the organic phase, dry with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure. The obtained solid is recrystallized from 300 ml of anhydrous ethanol to obtain yellow solid compound VII, with a yield of 84.8% and a HPLC purity of 98.88%.

[0104] Example 16

[0105] Add intermediate V (88.85 g, 0.17 mol), compound VI (37.53 g, 0.22 mol), triethylamine (17.20 g, 0.17 mol) and 500 mL of acetonitrile to a three-necked flask, stir to dissolve, reflux for 5 hours, stop heating, and slowly cool to room temperature. Add 500 mL of chloroform and 500 ml of purified water, shake vigorously and let stand, collect the organic phase, dry with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure. The obtained solid is recrystallized from 300 ml of anhydrous ethanol to obtain yellow solid compound VII, with a yield of 88.3% and a HPLC purity of 99.55%.

[0106] Example 16

[0107] Add intermediate V (88.85 g, 0.17 mol), compound VI (37.53 g, 0.22 mol), triethylamine (34.40 g, 0.34 mol) and 500 mL of dichloromethane to a three-necked flask, stir to dissolve, reflux for 5 hours, stop heating, and slowly cool to room temperature. Add 200 mL of dichloromethane and 500 ml of purified water, shake vigorously and let stand, collect the organic phase, dry with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure. The obtained solid is recrystallized from 300 ml of anhydrous ethanol to obtain yellow solid compound VII, with a yield of 87.8% and a HPLC purity of 99.42%.

[0108] Embodiment 17

[0109] Add intermediate V (88.85 g, 0.17 mol), compound VI (37.53 g, 0.22 mol), sodium methoxide (20.53 g, 0.38 mol) and 500 mL of cyclohexane to a three-necked flask, stir to dissolve, reflux for 5 hours, stop heating, and slowly cool to room temperature. Add 400 mL of ethyl acetate and 500 ml of purified water, shake vigorously and let stand, collect the organic phase, dry with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate under reduced pressure. The obtained solid is recrystallized from 300 ml of anhydrous ethanol to obtain yellow solid compound VII, with a yield of 84.4% and a HPLC purity of 98.82%.

[0110] Preparation of Compound VIII

[0111] Embodiment 18

[0112] Add intermediate VII (98.52 g, 0.15 mol), potassium hydroxide (12.90 g, 0.23 mol) and 500 mL N-methylpyrrolidone to a three-necked flask, react at 80°C to 85°C for 7 hours, stop heating, and slowly cool to room temperature. Add 500 mL ethyl acetate and 500 ml purified water, shake vigorously and let stand, collect the organic phase, concentrate the organic phase under reduced pressure, and recrystallize the obtained solid from ethyl acetate / n-hexane (volume ratio = 1:3, 400 ml) to obtain a yellow solid compound VIII with a yield of 98.4% and a HPLC purity of 99.62%.

[0113] Embodiment 19

[0114] Add intermediate VII (98.52 g, 0.15 mol), potassium carbonate (20.73 g, 0.15 mol) and 500 mL pyridine to a three-necked flask, react at 60°C to 65°C for 7 hours, stop heating, and slowly cool to room temperature. Add 500 mL ethyl acetate and 500 ml purified water, shake vigorously and let stand, collect the organic phase, concentrate the organic phase under reduced pressure, and recrystallize the obtained solid from ethyl acetate / n-hexane (volume ratio = 1:3, 400 ml) to obtain yellow solid compound VIII, with a yield of 94.2% and a HPLC purity of 99.41%.

[0115] Embodiment 20

[0116] Add intermediate VII (98.52 g, 0.15 mol), cesium carbonate (97.74 g, 0.30 mol) and 500 mL N, N-diethylaniline to a three-necked flask, react at 105°C to 110°C for 7 hours, stop heating, and slowly cool to room temperature. Add 500 mL of dichloromethane and 500 ml of purified water, shake vigorously and let stand, collect the organic phase, concentrate the organic phase under reduced pressure, and recrystallize the obtained solid from ethyl acetate / n-hexane (volume ratio = 1:3, 400 ml) to obtain a yellow solid compound VIII with a yield of 95.4% and a HPLC purity of 99.35%.

[0117] Embodiment 21

[0118] Add intermediate VII (98.52 g, 0.15 mol), potassium tert-butoxide (37.03 g, 0.33 mol) and 400 mL N, N-diethylaniline to a three-necked flask, react at 55°C to 60°C for 7 hours, stop heating, and slowly cool to room temperature. Add 500 mL of chloroform and 500 ml of purified water, shake vigorously and let stand, collect the organic phase, concentrate the organic phase under reduced pressure, and recrystallize the obtained solid from ethyl acetate / n-hexane (volume ratio = 1:3, 400 ml) to obtain a yellow solid compound VIII with a yield of 91.2% and a HPLC purity of 98.85%.

[0119] Preparation of Dehydrated Icariin

[0120] Embodiment 22

[0121] Compound VIII (70.26 g, 0.11 mol), 5% palladium carbon (21.2 g, 0.01 mol) and 200 ml of methanol were added to a three-necked flask, hydrogen was introduced, and the mixture was reacted at 40°C-45°C for 5 hours. The mixture was filtered, and 200 ml of purified water and 200 ml of ethyl acetate were added to the filtrate. After stirring and stratification, the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. 300 ml of methanol was added for recrystallization to obtain yellow solid dehydrated icariin with a yield of 94.6% and a HPLC purity of 99.87%.

[0122] Embodiment 23

[0123] Compound VIII (70.26 g, 0.11 mol), palladium hydroxide (1.54 g, 0.011 mol) and 200 ml of ethanol were added to a three-necked flask, hydrogen was introduced, and the mixture was reacted at 45°C-50°C for 5 hours. The mixture was filtered, and 200 ml of purified water and 200 ml of ethyl acetate were added to the filtrate. After stirring and stratification, the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. 300 ml of methanol was added for recrystallization to obtain yellow solid dehydrated icariin with a yield of 92.4% and a HPLC purity of 99.72%.

[0124] Embodiment 24

[0125] Compound VIII (70.26 g, 0.11 mol), palladium acetate (2.47 g, 0.011 mol) and 200 ml of 1,4-dioxane were added to a three-necked flask, hydrogen was introduced, and the mixture was reacted at 35°C to 40°C for 5 hours. The mixture was filtered, and 200 ml of purified water and 200 ml of dichloromethane were added to the filtrate. After stirring and stratification, the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. 300 ml of methanol was added for recrystallization to obtain yellow solid dehydrated icariin with a yield of 92.9% and a HPLC purity of 99.68%.

[0126] Embodiment 25

[0127] Compound VIII (70.26 g, 0.11 mol), 5% palladium carbon (11.71 g, 0.006 mol) and 200 ml of acetone were added to a three-necked flask, hydrogen was introduced, and the mixture was reacted at 20°C to 25°C for 5 hours. The mixture was filtered, and 200 ml of purified water and 200 ml of ethyl acetate were added to the filtrate. After stirring and stratification, the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. 300 ml of methanol was added for recrystallization to obtain yellow solid dehydrated icariin with a yield of 90.4% and a HPLC purity of 99.66%.

[0128] Embodiment 26

[0129] Compound VIII (70.26 g, 0.11 mol), 5% palladium on carbon (46.82 g, 0.022 mol) and 300 ml of tetrahydrofuran were added to a three-necked flask, hydrogen was introduced, and the mixture was reacted at 55°C-60°C for 5 hours. The mixture was filtered, and 300 ml of purified water and 300 ml of ethyl acetate were added to the filtrate. After stirring and stratification, the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. 300 ml of methanol was added for recrystallization to obtain yellow solid dehydrated icariin with a yield of 91.1% and a HPLC purity of 99.58%.

[0130] Embodiment 27

[0131] Compound VIII (70.26 g, 0.11 mol), 5% palladium on carbon (7.02 g, 0.0033 mol) and 200 ml of acetonitrile were added to a three-necked flask, hydrogen was introduced, and the mixture was reacted at 60°C-65°C for 5 hours. The mixture was filtered, and 300 ml of purified water and 300 ml of ethyl acetate were added to the filtrate. After stirring and stratification, the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. 300 ml of methanol was added for recrystallization to obtain yellow solid dehydrated icariin with a yield of 86.3% and a HPLC purity of 98.92%.

[0132] Embodiment 28

[0133] Compound VIII (70.26 g, 0.11 mol), 5% palladium carbon (58.53 g, 0.0275 mol) and 300 ml of dichloromethane were added to a three-necked flask, hydrogen was introduced, and the mixture was reacted at 15°C-20°C for 6 hours. The mixture was filtered, and 300 ml of purified water and 300 ml of chloroform were added to the filtrate. After stirring and stratification, the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. 300 ml of methanol was added for recrystallization to obtain yellow solid dehydrated icariin with a yield of 85.6% and a HPLC purity of 99.38%.

Claims

1. A dehydrated icariin intermediate compound, characterized in that: Its structure is shown in Formula IV: 。 2. A method for preparing the dehydrated icariin intermediate compound IV according to claim 1, characterized in that: The method comprises the following steps: adding compound II, compound III, a base and an organic solvent A into a reaction bottle, stirring to dissolve, controlling the temperature and stirring to react, and detecting that the reaction is complete to obtain compound IV; Wherein, the base is selected from one of cesium carbonate, potassium hydroxide, sodium hydroxide, potassium carbonate, and potassium tert-butoxide; The synthetic route is as follows: 。 3. The preparation method according to claim 2, characterized in that: The organic solvent A is selected from tetrahydrofuran, acetone, acetonitrile, toluene, xylene or a combination thereof; the reaction temperature is 50-100°C.

4. The preparation method according to claim 2, characterized in that: The molar ratio of the compound II, the compound III and the base is 1:1.0-1.8:1.0-2.

0.

5. Use of the dehydrated icariin intermediate compound IV according to claim 1 for preparing dehydrated icariin.

6. A method for preparing dehydrated icariin from the dehydrated icariin intermediate compound IV according to claim 5, characterized in that: The preparation method comprises the following steps: (1) Compound IV, a catalyst and an organic solvent B are added to a reaction flask and stirred at room temperature until the reaction is complete. The reaction is then post-treated to obtain compound V; (2) Compound V, compound VI, a base and an organic solvent C are added to a reaction flask, and heated under reflux until the reaction is complete to obtain an intermediate compound VII; (3) Compound VII, a base and an organic solvent D are added to a reaction bottle, heated and stirred, and heating is stopped after the reaction is complete to obtain compound VIII; (4) Compound VIII, a catalyst and an organic solvent E are added to a reaction flask, hydrogen is introduced into the flask, the temperature is controlled and stirred to react, and stirring is stopped after the reaction is detected to be complete, thereby obtaining dehydrated icariin. in The catalyst in step (1) is selected from bismuth trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, and europium trifluoromethanesulfonate; The base in step (2) is selected from the group consisting of triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, and sodium methoxide; The base in step (3) is selected from potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, and potassium tert-butoxide; The catalyst in step (4) is selected from palladium carbon, palladium hydroxide, and palladium acetate; The synthetic route is as follows: 。 7. The preparation method according to claim 6, characterized in that: The molar ratio of compound IV to catalyst in step (1) is 1:0.05-0.2; the organic solvent B is selected from tetrahydrofuran, acetonitrile, acetone, toluene, dichloromethane or a combination thereof.

8. The preparation method according to claim 6, characterized in that: In step (2), the molar ratio of compound V, compound VI and base is 1:1.0-2.0:1.0-2.0; the organic solvent C is selected from one of acetone, tetrahydrofuran, acetonitrile, dichloromethane and cyclohexane or a combination thereof.

9. The preparation method according to claim 6, characterized in that: The molar ratio of compound VII and base in step (3) is 1:1.0-2.0; the organic solvent D is selected from pyridine, N,N -Diethylaniline, N -methyl pyrrolidone or a combination thereof; the reaction temperature is 60°C to 110°C.

10. The preparation method according to claim 6, characterized in that: The molar ratio of compound VIII to the catalyst in step (4) is 1:0.05-0.2; the organic solvent E is selected from one of methanol, ethanol, acetone, tetrahydrofuran, acetonitrile, dichloromethane, 1,4-dioxane or a combination thereof; and the reaction temperature is 20°C-60°C.

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