CN114539044A - Dehydrated icaritin intermediate compound - Google Patents

Dehydrated icaritin intermediate compound Download PDF

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CN114539044A
CN114539044A CN202011334477.5A CN202011334477A CN114539044A CN 114539044 A CN114539044 A CN 114539044A CN 202011334477 A CN202011334477 A CN 202011334477A CN 114539044 A CN114539044 A CN 114539044A
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compound
reaction
organic solvent
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anhydroicaritin
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隋月波
王本利
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • 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

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a dehydrated icaritin intermediate compound. The invention takes 2- (benzyloxy) -1- (2, 4-bis (benzyloxy) -6-hydroxyphenyl) ethan-1-one as an initial raw material, and reacts with 1-bromo-3-methylbut-2-ene under the action of a catalyst to obtain a new intermediate 2- (benzyloxy) -1- (2, 4-bis (benzyloxy) -6- ((3-methylbut-2-en-1-yl) oxy) phenyl) ethan-1-one of anhydroicaritin. Meanwhile, the invention provides a method for preparing the anhydroicaritin by using the new intermediate compound, which comprises the following steps: the 2- (benzyloxy) -1- (2, 4-bis (benzyloxy) -6- ((3-methylbut-2-alkene-1-yl) oxy) phenyl) ethane-1-ketone has rearrangement reaction and then reacts with 4-methoxy benzoyl chloride, and the dehydrated icariin is obtained after cyclization and debenzylation of the obtained product. The synthesis method of the new intermediate provided by the invention is simple, isopentenyl is introduced into the intermediate before the flavone skeleton is formed by introducing the protecting group, and the protecting group can be removed in one step finally to obtain the dehydrated icariin. The synthesis method has the advantages of short synthesis route, high yield, mild reaction conditions and stable process, and is suitable for mass industrial production.

Description

Dehydrated icaritin intermediate compound
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a dehydrated icaritin intermediate compound.
Background
Anhydroicaritin (Icariin), chemical name is 3,5, 7-trihydroxy-2- (4-methoxybenzene) -8- (3-methylbut-2-ene) chalcone-4-ketone, molecular formula: c21H20O6(ii) a Molecular weight: 368.13, respectively; CAS number 118525-40-9, structural formula as follows:
Figure BDA0002796758080000011
the anhydroicaritin belongs to flavonol compounds, is commonly present in plants, has a large quantity and a complex and various structure, and has a plurality of important biological activities and pharmacological actions. Such as anti-tumor, anti-cancer cell proliferation, anti-osteoporosis, estrogen regulation, nervous system regulation, etc. At present, icaritin is mainly extracted from plants, but the content of the natural product is low, and the separation and purification are complex, so that the development in the field of medicine is limited. The total synthesis of the single compound of anhydroicaritin solves the problem and provides guarantee for clinical tests planned by the next step and possible drug use.
The prior art has few related reports about total synthesis of icaritin, and Chinese patent application CN200610165354.7 discloses a synthesis method of icaritin, the route takes kaempferol-4-oxygen methyl ether as a starting material to prepare the icaritin, and the synthesis steps introduced by the patent are as follows:
Figure BDA0002796758080000012
however, in the above method, the synthesis of kaempferol-4-oxymethyl ether requires eight steps of reaction, and the operation is complicated. The claisen rearrangement needs microwave heating to be carried out, the production cost is high, and the large-scale industrial production is not facilitated.
An article entitled "synthesis of icaritin" was disclosed in organic chemistry, 3 months 2013, and mentions 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-octanedione) europium was used as a catalyst with a yield of 42%. The catalyst is expensive and has low reaction yield, which is not beneficial to industrial production. How to optimize or avoid claisen rearrangement becomes a key to this synthetic route.
Chinese patent application CN201910220551.1 reports that isopentenyl group is connected to 8-carbon by ortho-rearrangement, and then a series of reactions of formation of flavone skeleton are performed to obtain anhydroicaritin, which introduces the following synthetic steps:
Figure BDA0002796758080000021
although the reaction conditions are mild, the synthetic route is long, the introduction and removal of the protecting group are difficult, and the purification and the industrial production are not facilitated.
Disclosure of Invention
At present, the synthesis of epimedium compounds has various defects such as difficult introduction of isopentenyl, difficult removal of protecting groups, complex process, expensive catalyst, more byproducts and the like. The invention provides a novel dehydrated icaritin intermediate compound and a preparation method thereof. The intermediate is used for synthesizing the anhydroicaritin, and has the advantages of short route, high yield, mild reaction conditions and stable process, and is suitable for large-scale industrial production.
The invention is realized by the following technical scheme:
the invention provides a novel dehydrated icaritin intermediate compound in a first aspect, which has a structure shown in a formula IV:
Figure BDA0002796758080000031
in a second aspect, the present invention provides a process for the preparation of compound IV, comprising the steps of:
adding a compound II, a compound III, alkali and an organic solvent A into a reaction bottle, stirring and dissolving, controlling the temperature, stirring and reacting, and obtaining a compound IV after complete detection reaction, wherein the synthetic route is as follows:
Figure BDA0002796758080000032
preferably, the base is selected from one of cesium carbonate, potassium hydroxide, sodium hydroxide, potassium carbonate and potassium tert-butoxide, wherein cesium carbonate is particularly preferred.
Preferably, the feeding molar ratio of the compound II to the compound III to the base is 1: 1.0-1.8: 1.0-2.0, and particularly preferably 1:1.2: 1.1.
Preferably, the organic solvent A is selected from one or a combination of tetrahydrofuran, acetone, acetonitrile, toluene and xylene.
Preferably, the reaction temperature is 50-100 ℃, and particularly preferably 80-85 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: adding purified water and an extracting agent into the reaction solution, separating liquid, collecting an organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain a compound IV; the extractant is one or the combination of ethyl acetate, dichloromethane and trichloromethane.
The third aspect of the invention provides application of a compound IV in preparing anhydroicaritin.
The method for preparing the dehydrated icariin by using the compound IV comprises the following scheme: obtaining an intermediate V from the intermediate IV under the action of a catalyst; obtaining a compound VII by the intermediate V and the compound VI under the action of alkalinity; performing cyclization reaction on the compound VII under an alkaline condition to obtain an intermediate VIII; the intermediate VIII is subjected to reduction reaction to remove benzyl to obtain the dehydrated icariin, and the synthetic route is as follows:
Figure BDA0002796758080000041
preferably, the above steps are described in further detail in the following sections:
preparation of Compound V
The preparation method of the compound V comprises the following steps: adding the compound IV, a catalyst and an organic solvent B into a reaction bottle, stirring at room temperature until the reaction is finished, and carrying out post-treatment on the reaction to obtain a compound V;
preferably, the catalyst is selected from one of bismuth triflate, ytterbium triflate, scandium triflate and europium triflate, wherein bismuth triflate is particularly preferred.
Preferably, the feeding molar ratio of the compound IV to the catalyst is 1:0.05 to 0.2, wherein 1: 0.1.
preferably, the organic solvent is one or a combination of B tetrahydrofuran, acetonitrile, acetone, toluene and dichloromethane.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: adding the reaction solution into purified water, adding an extracting agent, collecting an organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain an intermediate V; the extractant is one or the combination of ethyl acetate, dichloromethane and trichloromethane.
Preparation of Compound VII
Adding the compound V, the compound VI, alkali and an organic solvent into a reaction bottle, and heating and refluxing until the reaction is finished to obtain an intermediate compound VII;
preferably, the base is selected from one of triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide and sodium methoxide, and triethylamine is particularly preferred.
Preferably, the feeding molar ratio of the compound V, the compound VI and the base is 1: 1.0-2.0, and particularly preferably 1:1.3: 1.5.
Preferably, the organic solvent C is selected from one or a combination of acetone, tetrahydrofuran, acetonitrile, dichloromethane and cyclohexane.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: cooling the reaction liquid to room temperature, adding purified water and an extracting agent, collecting an organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering to remove a drying agent, and adding the obtained solid into ethanol for recrystallization to obtain a compound VII after vacuum concentration; the extractant is one or the combination of ethyl acetate, dichloromethane and trichloromethane.
Preparation of Compound VIII
Adding a compound VII, alkali and an organic solvent D into a reaction bottle, heating and stirring, and stopping heating after detecting that the reaction is complete to obtain a compound VIII;
preferably, the base is selected from one of potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate and potassium tert-butoxide, with potassium hydroxide being particularly preferred.
Preferably, the feeding molar ratio of the compound VII to the base is 1: 1.0-2.0, and particularly preferably 1: 1.5.
Preferably, the solvent D is selected from one or a combination of pyridine, N-diethylaniline and N-methylpyrrolidone.
Preferably, the reaction temperature is 60 ℃ to 110 ℃, particularly preferably 80 ℃ to 85 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: cooling the reaction liquid to room temperature, adding an extracting agent, collecting an organic phase, concentrating the organic phase under reduced pressure, and recrystallizing with ethyl acetate/n-hexane (volume ratio 1:3) to obtain a compound VIII; the extractant is one or the combination of ethyl acetate, dichloromethane and trichloromethane.
Preparation of dehydrated icaritin
Adding the compound VIII, a catalyst and an organic solvent E into a reaction bottle, introducing hydrogen into the bottle, stirring and reacting at controlled temperature, and stopping stirring after detecting that the reaction is complete to obtain the dehydrated icariin.
Preferably, the catalyst is selected from one of palladium carbon, palladium hydroxide and palladium acetate, wherein palladium carbon is particularly preferred.
Preferably, the feeding molar ratio of the compound VIII to the catalyst is 1: 0.05-0.2, wherein 1:0.10 is particularly preferred
Preferably, the organic solvent E is selected from one of methanol, ethanol, acetone, tetrahydrofuran, acetonitrile, dichloromethane and 1, 4-dioxane or the combination thereof.
Preferably, the reaction temperature is 20-60 DEG C
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: filtering the reaction solution, collecting an organic phase, adding purified water and an extracting agent into the organic phase, drying the collected organic phase by using anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and recrystallizing the obtained solid by using methanol to obtain dehydrated icaritin; the extractant is one or the combination of ethyl acetate, dichloromethane and trichloromethane.
The invention has the following beneficial effects:
1. the invention provides a novel anhydroicaritin intermediate compound and a preparation method thereof, and the anhydroicaritin prepared from the novel intermediate has short reaction route and high yield.
2. The preparation method of the anhydroicaritin provided by the invention introduces isopentenyl group before the flavone skeleton is formed, so that the selectivity of the isopentenyl group is improved; the compound VII is subjected to cyclization reaction under alkaline condition to obtain an intermediate VIII, and complex operations such as a guide group, a pre-activated reaction site and the like in the prior art are avoided.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
The structure of the compound obtained by the invention is confirmed:
Figure BDA0002796758080000061
high resolution mass spectrum of compound IV: ESI-HRMS: M/z 523.6212[ M + H ]]+,1H-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)；13C-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.
Figure BDA0002796758080000062
High resolution mass spectrum of compound V: ESI-HRMS: M/z 523.2402[ M + H ]]+,1H-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)；13C-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.
Figure BDA0002796758080000071
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)；13C-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.
Figure BDA0002796758080000072
High resolution mass spectrum of compound VIII: ESI-HRMS: M/z 639.6213[ M + H ]]+,1H-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)；13C-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.
Figure BDA0002796758080000073
High resolution mass spectrum of compound I: ESI-HRMS: M/z 368.1263[ M + H ]]+,1H-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)；13C-NMR(100MHz,CDCl3):δ176.6,161.4,160.7,158.5,153.9,146.5,136.4,131.5,129.6,124.1,122.9,114.6,106.1,103.6,98.3,55.9,25.3,21.8,18.4.
Preparation of Compound IV
Example 1
Adding the intermediate II (142.00g, 0.31mol), the compound III (55.14g, 0.37mol), cesium carbonate (110.78g, 0.34mol) and 1000mL of toluene into a three-necked flask, stirring for dissolving, reacting at 80-85 ℃ for 6 hours, slowly cooling the reaction liquid to room temperature, adding 600mL of purified water and 500mL of ethyl acetate, violently shaking, standing, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain a white solid powdery compound IV, wherein the yield is 90.1%, and the HPLC purity is 99.78%.
Example 2
Adding the intermediate II (142.00g, 0.31mol), the compound III (46.20g, 0.31mol), potassium hydroxide (19.08g, 0.34mol) and 500mL of toluene into a three-necked flask, stirring for dissolving, reacting at 50-55 ℃ for 6 hours, slowly cooling the reaction liquid to room temperature, adding 400mL of purified water and 300mL of ethyl acetate, violently shaking, standing, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain a white solid powdery compound IV, wherein the yield is 87.3% and the HPLC purity is 99.36%.
Example 3
Adding the intermediate II (142.00g, 0.31mol), the compound III (83.46g, 0.56mol), potassium carbonate (46.99g, 0.34mol) and 500mL of p-xylene into a three-necked flask, stirring for dissolving, reacting at 95-100 ℃ for 6 hours, slowly cooling the reaction liquid to room temperature, adding 400mL of purified water and 400mL of ethyl acetate, violently shaking, standing, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain a white solid powdery compound IV with the yield of 86.9% and the HPLC purity of 99.28%.
Example 4
Adding the intermediate II (142.00g, 0.31mol), the compound III (92.40g, 0.62mol), potassium tert-butoxide (76.30g, 0.68mol) and 500mL of toluene into a three-necked flask, stirring for dissolving, reacting at 100-105 ℃ for 4 hours, slowly cooling the reaction solution to room temperature, adding 500mL of purified water and 600mL of ethyl acetate, violently shaking, standing, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain a white solid powdery compound IV with the yield of 81.5% and the HPLC purity of 98.82%.
Example 5
Adding the intermediate II (142.00g, 0.31mol), the compound III (55.14g, 0.37mol), cesium carbonate (101.0g, 0.31mol) and 1000mL of tetrahydrofuran into a three-necked flask, stirring for dissolving, reacting at 55-60 ℃ for 6 hours, slowly cooling the reaction liquid to room temperature, adding 600mL of purified water and 500mL of dichloromethane, violently shaking, standing, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain a white solid powdery compound IV, wherein the yield is 88.7%, and the HPLC purity is 99.53%.
Example 6
Adding the intermediate II (142.00g, 0.31mol), the compound III (55.14g, 0.37mol), cesium carbonate (202.0g, 0.62mol) and 1200mL of acetonitrile into a three-necked flask, stirring for dissolving, reacting at 75-80 ℃ for 6 hours, slowly cooling the reaction liquid to room temperature, adding 600mL of purified water and 600mL of trichloromethane, violently shaking, standing, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain a white solid powdery compound IV, wherein the yield is 86.9% and the HPLC purity is 99.38%.
Example 7
Adding the intermediate II (142.00g, 0.31mol), the compound III (55.14g, 0.37mol), cesium carbonate (221.56g, 0.68mol) and 1300mL of acetone into a three-necked flask, stirring for dissolving, reacting at 45-50 ℃ for 6 hours, slowly cooling the reaction liquid to room temperature, adding 600mL of purified water and 600mL of trichloromethane, violently shaking, standing, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain a white solid powdery compound IV, wherein the yield is 82.3%, and the HPLC purity is 98.64%.
Preparation of Compound V
Example 8
Compound IV (132.21g, 0.25mol), bismuth trifluoromethanesulfonate (16.40g, 0.025mol) and 500mL of dichloromethane were added to a three-necked flask, stirred at room temperature until the reaction was completed, to which 500mL of purified water and 500mL of ethyl acetate were added, followed by vigorous shaking and standing, the organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to give compound V as a yellow solid in 88.3% yield and 99.61% purity by HPLC.
Example 8
Compound IV (132.21g, 0.25mol), bismuth trifluoromethanesulfonate (8.20g, 0.0125mol) and 400mL of tetrahydrofuran were added to a three-necked flask, and stirred at room temperature until the reaction was completed, 300mL of purified water and 300mL of dichloromethane were added thereto, followed by vigorous shaking, standing, collecting the organic phase, drying with anhydrous sodium sulfate, filtering to remove the drying agent, and concentrating under reduced pressure to obtain compound V as a yellow solid in 84.6% yield and 99.38% purity by HPLC.
Example 9
Compound IV (132.21g, 0.25mol), ytterbium triflate (31.01g, 0.05mol), 500mL acetonitrile were added to a three-necked flask, stirred at room temperature until the reaction was completed, 500mL purified water and 500mL dichloromethane were added thereto, vigorously shaken and then allowed to stand, the organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain yellow solid compound V, yield 85.2%, purity by HPLC 99.32%.
Example 10
Compound IV (132.21g, 0.25mol), scandium trifluoromethanesulfonate (3.69g, 0.0075mol) and 300mL of acetone were added to a three-necked flask, and stirred at room temperature until the reaction was completed, 300mL of purified water and 300mL of chloroform were added thereto, and after vigorous shaking, the mixture was allowed to stand, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain compound V as a yellow solid, in 79.8% yield and 98.95% purity by HPLC.
Example 11
Compound IV (132.21g, 0.25mol), europium triflate (32.95g, 0.055mol) and 500mL acetone were added to a three-necked flask, stirred at room temperature until the reaction was completed, 400mL purified water and 400mL chloroform were added thereto, vigorously shaken and then allowed to stand, the organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain compound V as a yellow solid in 80.2% yield and 98.99% purity by HPLC.
Preparation of Compound VII
Example 12
Intermediate V (88.85g, 0.17mol), Compound VI (37.53g, 0.22mol), triethylamine (26.31g, 0.26mol) and 500mL tetrahydrofuran were added to a three-necked flask, dissolved with stirring, refluxed for 5 hours, stopped heating, and slowly cooled to room temperature. Adding 500mL of ethyl acetate and 500mL of purified water, shaking vigorously, standing, collecting the organic phase, drying with anhydrous sodium sulfate, filtering to remove the drying agent, concentrating under reduced pressure, and recrystallizing the obtained solid with 300mL of anhydrous ethanol to obtain a yellow solid compound VII with the yield of 92.1% and the HPLC purity of 99.96%.
Example 13
Intermediate V (88.85g, 0.17mol), Compound VI (29.0g, 0.17mol), potassium hydroxide (14.59g, 0.26mol) and 500mL tetrahydrofuran were added to a three-necked flask, dissolved with stirring, refluxed for 5 hours, quenched, and slowly cooled to room temperature. Adding 500mL of ethyl acetate and 500mL of purified water, shaking vigorously, standing, collecting the organic phase, drying with anhydrous sodium sulfate, filtering to remove the drying agent, concentrating under reduced pressure, and recrystallizing the obtained solid with 300mL of anhydrous ethanol to obtain a yellow solid compound VII with the yield of 88.6% and the HPLC purity of 99.71%.
Example 14
Intermediate V (88.85g, 0.17mol), Compound VI (58.0g, 0.34mol), potassium carbonate (35.93g, 0.26mol) and 500mL tetrahydrofuran were added to a three-necked flask, dissolved with stirring, refluxed for 5 hours, quenched, and slowly cooled to room temperature. Adding 500mL of ethyl acetate and 500mL of purified water, shaking vigorously, standing, collecting the organic phase, drying with anhydrous sodium sulfate, filtering to remove the drying agent, concentrating under reduced pressure, and recrystallizing the obtained solid with 300mL of anhydrous ethanol to obtain a yellow solid compound VII with yield of 89.2% and HPLC purity of 99.58%.
Example 15
Intermediate V (88.85g, 0.17mol), Compound VI (64.82g, 0.38mol), potassium tert-butoxide (42.64g, 0.38mol) and 500mL of tetrahydrofuran were added to a three-necked flask, dissolved with stirring, refluxed for 5 hours, quenched, and slowly cooled to room temperature. Adding 500mL of dichloromethane and 500mL of purified water, violently shaking and standing, collecting an organic phase, drying by using anhydrous sodium sulfate, filtering to remove a drying agent, concentrating under reduced pressure, and recrystallizing the obtained solid by using 300mL of anhydrous ethanol to obtain a yellow solid compound VII, wherein the yield is 84.8%, and the HPLC purity is 98.88%.
Example 16
Intermediate V (88.85g, 0.17mol), Compound VI (37.53g, 0.22mol), triethylamine (17.20g, 0.17mol) and 500mL acetonitrile were added to a three-necked flask, dissolved with stirring, refluxed for 5 hours, stopped heating, and slowly cooled to room temperature. Adding 500mL of trichloromethane and 500mL of purified water, shaking vigorously, standing, collecting an organic phase, drying with anhydrous sodium sulfate, filtering to remove a drying agent, concentrating under reduced pressure, and recrystallizing the obtained solid with 300mL of anhydrous ethanol to obtain a yellow solid compound VII with the yield of 88.3% and the HPLC purity of 99.55%.
Example 16
Intermediate V (88.85g, 0.17mol), Compound VI (37.53g, 0.22mol), triethylamine (34.40g, 0.34mol) and 500mL of dichloromethane were added to a three-necked flask, dissolved with stirring, refluxed for 5 hours, stopped heating, and slowly cooled to room temperature. Adding 200mL of dichloromethane and 500mL of purified water, violently shaking and standing, collecting an organic phase, drying by using anhydrous sodium sulfate, filtering to remove a drying agent, concentrating under reduced pressure, and recrystallizing the obtained solid by using 300mL of anhydrous ethanol to obtain a yellow solid compound VII, wherein the yield is 87.8%, and the HPLC purity is 99.42%.
Example 17
Intermediate V (88.85g, 0.17mol), Compound VI (37.53g, 0.22mol), sodium methoxide (20.53g, 0.38mol) and 500mL cyclohexane were added to a three-necked flask, dissolved with stirring, refluxed for 5 hours, stopped heating, and slowly cooled to room temperature. Adding 400mL of ethyl acetate and 500mL of purified water, violently shaking and standing, collecting an organic phase, drying by using anhydrous sodium sulfate, filtering to remove a drying agent, concentrating under reduced pressure, and recrystallizing the obtained solid by using 300mL of anhydrous ethanol to obtain a yellow solid compound VII, wherein the yield is 84.4%, and the HPLC purity is 98.82%.
Preparation of Compound VIII
Example 18
Adding the intermediate VII (98.52g, 0.15mol), potassium hydroxide (12.90g, 0.23mol) and 500ml of N-methyl pyrrolidone into a three-neck flask, reacting at 80-85 ℃ for 7 hours, stopping heating, and slowly cooling to room temperature. Adding 500mL of ethyl acetate and 500mL of purified water, shaking vigorously, standing, collecting an organic phase, concentrating the organic phase under reduced pressure, and recrystallizing the obtained solid with ethyl acetate/n-hexane (volume ratio is 1:3, 400mL) to obtain a yellow solid compound VIII, wherein the yield is 98.4% and the HPLC purity is 99.62%.
Example 19
Intermediate VII (98.52g, 0.15mol), potassium carbonate (20.73g, 0.15mol) and 500mL of pyridine were added to a three-necked flask, reacted at 60 ℃ to 65 ℃ for 7 hours, the heating was stopped, and the temperature was slowly decreased to room temperature. Adding 500mL of ethyl acetate and 500mL of purified water, shaking vigorously, standing, collecting an organic phase, concentrating the organic phase under reduced pressure, and recrystallizing the obtained solid with ethyl acetate/n-hexane (volume ratio is 1:3, 400mL) to obtain a yellow solid compound VIII, wherein the yield is 94.2%, and the HPLC purity is 99.41%.
Example 20
Intermediate VII (98.52g, 0.15mol), cesium carbonate (97.74g, 0.30mol) and 500mL of N, N-diethylaniline were added to a three-necked flask, and reacted at 105 ℃ to 110 ℃ for 7 hours, and heating was stopped and the temperature was slowly decreased to room temperature. Adding 500mL of dichloromethane and 500mL of purified water, shaking vigorously, standing, collecting an organic phase, concentrating the organic phase under reduced pressure, and recrystallizing the obtained solid with ethyl acetate/n-hexane (volume ratio is 1:3, 400mL) to obtain a yellow solid compound VIII, wherein the yield is 95.4% and the HPLC purity is 99.35%.
Example 21
A three-necked flask was charged with intermediate VII (98.52g, 0.15mol), potassium tert-butoxide (37.03g, 0.33mol) and 400mL of N, N-diethylaniline, reacted at 55 ℃ to 60 ℃ for 7 hours, and the heating was stopped and the temperature was slowly lowered to room temperature. Adding 500mL of trichloromethane and 500mL of purified water, shaking vigorously, standing, collecting an organic phase, concentrating the organic phase under reduced pressure, and recrystallizing the obtained solid with ethyl acetate/n-hexane (volume ratio is 1:3, 400mL) to obtain a yellow solid compound VIII, wherein the yield is 91.2%, and the HPLC purity is 98.85%.
Preparation of dehydrated icaritin
Example 22
Adding compound VIII (70.26g, 0.11mol), 5% palladium carbon (21.2g, 0.01mol) and 200ml of methanol into a three-necked flask, introducing hydrogen, reacting at 40-45 ℃ for 5 hours, performing suction filtration, adding 200ml of purified water and 200ml of ethyl acetate into filtrate, stirring and layering, collecting an organic layer, drying the organic layer by anhydrous sodium sulfate, concentrating to dryness, adding 300ml of methanol for recrystallization, and obtaining yellow solid dehydrated icaritin with the yield of 94.6% and the HPLC purity of 99.87%.
Example 23
Adding the compound VIII (70.26g, 0.11mol), palladium hydroxide (1.54g, 0.011mol) and 200ml ethanol into a three-necked flask, introducing hydrogen, reacting at 45-50 ℃ for 5 hours, performing suction filtration, adding 200ml purified water and 200ml ethyl acetate into filtrate, stirring, layering, collecting an organic layer, drying the organic layer by anhydrous sodium sulfate, concentrating to dryness, adding 300ml methanol, and recrystallizing to obtain yellow solid dehydrated icaritin, wherein the yield is 92.4%, and the HPLC purity is 99.72%.
Example 24
Adding compound VIII (70.26g, 0.11mol), palladium acetate (2.47g, 0.011mol) and 200ml of 1, 4-dioxane into a three-neck flask, introducing hydrogen, reacting for 5 hours at 35-40 ℃, performing suction filtration, adding 200ml of purified water and 200ml of dichloromethane into filtrate, stirring for layering, collecting an organic layer, drying the organic layer by anhydrous sodium sulfate, concentrating to dryness, adding 300ml of methanol for recrystallization, and obtaining yellow solid dehydrated icaritin, wherein the yield is 92.9%, and the HPLC purity is 99.68%.
Example 25
Adding the compound VIII (70.26g, 0.11mol), 5% palladium carbon (11.71g, 0.006mol) and 200ml of acetone into a three-neck flask, introducing hydrogen, reacting at 20-25 ℃ for 5 hours, performing suction filtration, adding 200ml of purified water and 200ml of ethyl acetate into filtrate, stirring for layering, collecting an organic layer, drying the organic layer by anhydrous sodium sulfate, concentrating to dryness, adding 300ml of methanol for recrystallization, and obtaining yellow solid dehydrated icariin with the yield of 90.4% and the HPLC purity of 99.66%.
Example 26
Adding compound VIII (70.26g, 0.11mol), 5% palladium carbon (46.82g, 0.022mol) and 300ml tetrahydrofuran into a three-necked flask, introducing hydrogen, reacting at 55-60 ℃ for 5 hours, performing suction filtration, adding 300ml purified water and 300ml ethyl acetate into filtrate, stirring for layering, collecting an organic layer, drying the organic layer by anhydrous sodium sulfate, concentrating to dryness, adding 300ml methanol for recrystallization, and obtaining yellow solid anhydroicaritin with the yield of 91.1% and the HPLC purity of 99.58%.
Example 27
Adding compound VIII (70.26g, 0.11mol), 5% palladium carbon (7.02g, 0.0033mol) and 200ml acetonitrile into a three-necked bottle, introducing hydrogen, reacting at 60-65 ℃ for 5 hours, performing suction filtration, adding 300ml of purified water and 300ml of ethyl acetate into filtrate, stirring for layering, collecting an organic layer, drying the organic layer by anhydrous sodium sulfate, concentrating to dryness, adding 300ml of methanol for recrystallization, and obtaining yellow solid dehydrated icariin, wherein the yield is 86.3%, and the HPLC purity is 98.92%.
Example 28
Adding compound VIII (70.26g, 0.11mol), 5% palladium carbon (58.53g, 0.0275mol) and 300ml dichloromethane into a three-necked flask, introducing hydrogen, reacting at 15-20 ℃ for 6 hours, performing suction filtration, adding 300ml purified water and 300ml chloroform into filtrate, stirring and layering, collecting an organic layer, drying the organic layer by anhydrous sodium sulfate, concentrating to dryness, adding 300ml methanol, and recrystallizing to obtain yellow solid anhydroicaritin, wherein the yield is 85.6%, and the HPLC purity is 99.38%.

Claims (10)

1. A dehydrated icaritin intermediate compound is characterized in that the structure is shown as formula IV:
Figure FDA0002796758070000011
2. a method of preparing anhydroicaritin intermediate compound IV of claim 1, comprising the steps of: adding a compound II, a compound III, alkali and an organic solvent A into a reaction bottle, stirring and dissolving, controlling the temperature, stirring and reacting, and obtaining a compound IV after complete detection reaction, wherein the synthetic route is as follows:
Figure FDA0002796758070000012
3. the preparation method according to claim 2, wherein the base is one selected from cesium carbonate, potassium hydroxide, sodium hydroxide, potassium carbonate, and potassium tert-butoxide; the organic solvent A is one or the combination of tetrahydrofuran, acetone, acetonitrile, toluene and xylene; the reaction temperature is 50-100 ℃.
4. The preparation method according to claim 2, wherein the feeding molar ratio of the compound II to the compound III to the base is 1: 1.0-1.8: 1.0-2.0.
5. Use of anhydroicaritin intermediate compound IV of claim 1 for the preparation of anhydroicaritin.
6. Use of anhydroicaritin intermediate compound IV of claim 5 for the preparation of anhydroicaritin comprising the steps of:
(1) adding the compound IV, a catalyst and an organic solvent B into a reaction bottle, stirring at room temperature until the reaction is finished, and carrying out post-treatment on the reaction to obtain a compound V;
(2) adding the compound V, the compound VI, alkali and an organic solvent C into a reaction bottle, and heating and refluxing until the reaction is finished to obtain an intermediate compound VII;
(3) adding a compound VII, alkali and an organic solvent D into a reaction bottle, heating and stirring, and stopping heating after detecting that the reaction is complete to obtain a compound VIII;
(4) adding a compound VIII, a catalyst and an organic solvent E into a reaction bottle, introducing hydrogen into the bottle, stirring and reacting at controlled temperature, stopping stirring after detecting that the reaction is complete, and obtaining the dehydrated icaritin, wherein the synthetic route is as follows:
Figure FDA0002796758070000021
7. the use according to claim 6, wherein the catalyst in step (1) is selected from one of bismuth triflate, ytterbium triflate, scandium triflate, europium triflate; the feeding molar ratio of the compound IV to the catalyst is 1:0.05 to 0.2; the organic solvent B is one or the combination of tetrahydrofuran, acetonitrile, acetone, toluene and dichloromethane.
8. The use according to claim 6, wherein the base in step (2) is selected from one of triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium methoxide; the feeding molar ratio of the compound V to the compound VI to the alkali is 1: 1.0-2.0; the organic solvent C is selected from one or the combination of acetone, tetrahydrofuran, acetonitrile, dichloromethane and cyclohexane.
9. The use according to claim 6, wherein the base in step (3) is selected from one of potassium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, potassium tert-butoxide; the feeding molar ratio of the compound VII to the alkali is 1: 1.0-2.0; the organic solvent D is selected from one or the combination of pyridine, N-diethylaniline and N-methylpyrrolidone; the reaction temperature is 60-110 ℃.
10. The use according to claim 6, wherein the catalyst in step (4) is selected from one of palladium carbon, palladium hydroxide and palladium acetate; the feeding molar ratio of the compound VIII to the catalyst is 1: 0.05-0.2; the organic solvent E is selected from one or the combination of methanol, ethanol, acetone, tetrahydrofuran, acetonitrile, dichloromethane and 1, 4-dioxane; the reaction temperature is 20-60 ℃.
CN202011334477.5A 2020-11-24 2020-11-24 Dehydrated icaritin intermediate compound Pending CN114539044A (en)

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