CN1448400A - Synthetic method of 24-methylene-cholesterol-3 beta, 5 alpha, 6 beta,19-tetraalcohol - Google Patents

Synthetic method of 24-methylene-cholesterol-3 beta, 5 alpha, 6 beta,19-tetraalcohol Download PDF

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CN1448400A
CN1448400A CN 03114370 CN03114370A CN1448400A CN 1448400 A CN1448400 A CN 1448400A CN 03114370 CN03114370 CN 03114370 CN 03114370 A CN03114370 A CN 03114370A CN 1448400 A CN1448400 A CN 1448400A
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ketone
courage steroid
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苏镜娱
陆伟刚
曾陇梅
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Sun Yat Sen University
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Abstract

The synthesis process of natural product 24-methene-cholest-3beta, 5alpha, 6beta, 19-tetrol (Nephalserol A) with antitumor and antiseptic activity includes the steps of: synthesis of 3beta-acetoxy-cholest-5-ene-24-one with easy-to-obtain stigmacholest; reaction of 3beta-acetoxy-cholest-5-ene-24-one with N-bromoacetamide in the catalysis of water solution of perchloric acid to produce 3beta-acetoxy-cholest-5alpha-bromo-6beta-hydroxy-24-one; photoannulation reaction to produce 3beta-acetoxy-cholest-5alpha-bromo-6, 19-epoxy-24-one; epoxy ring-opening reaction to produce 3beta-acetoxy-cholest-5-ene-19-hydroxy-24-one; oxidation of 5, 6-double bond with formic acid to obtain 3beta, 5alpha, 6beta, 19-tetrahydroxy-cholest-24-one; and final transforming the carbonyl group in 24-th place of branch chain into methane to obtain the destination product. The present invention has total yield of 9.3 %.

Description

24-methylene radical-courage steroid-3 β, 5 α, 6 β, the synthetic method of 19-tetrol
Technical field
The present invention relates to have natural product 24-methylene radical-courage steroid-3 β of remarkable physiologically active, 5 α, 6 β, 19-tetrol (24-methylene-cholest-3 β, 5 α, 6 β, 19-tetrol; NephalsterolA) artificial synthesis.
Background technology
24-methylene radical-courage steroid-3 β; 5 α; 6 β; (structure is suc as formula shown in the I for the 19-tetrol; hereinafter to be referred as formula I compound) at first be that once people such as Gansu Province plum separated from South Sea soft coral Nephthea albida and N.tiexieral verseveldt and obtains that (Wang Guiyang gives birth to; Li Fengying; once Gansu Province plum etc.; SCI; 1992,13,623-627); this natural product all has powerful poisoning ability, ED to human body rectum cancer cell, human body lung carcinoma cell, human oral cavity cancer cells and muroid lymphocytic cancer cell 50Value is respectively 0.81,0.93,0.39 and 0.34 μ g/mL (ED 50≤ 4.0 μ g/mL significantly suppress, Chang-Yih Duh, and Shang-Kwei Wang, Mei-Jen Chu et al., J. Nat.Prod, 1998,61,1022-1024); And to multiple inflammation have significant anti-inflammatory action (Wang Zhenglian, Xu Shibo, Liu Qing etc., tropical ocean, 1999,18,27-32).
24-methylene radical-courage steroid-3 β, 5 α, 6 β, the content of 19-tetrol in marine organisms is very little, once Gansu Province plum etc. was divided into from 8.0kg soft coral Nephtheatiexieral verseveldt from obtaining this compound of 0.2g, and the halobiontic quantity of this kind is few, is difficult for a large amount of the collection, so directly utilize marine organisms to be difficult to satisfy the demand of society now as this compound of raw material separation and Extraction.
Summary of the invention
The purpose of this invention is to provide a kind of Synthetic 2 4-methylene radical-courage steroid-3 β, 5 α, 6 β, the method for 19-tetrol.
Method of the present invention is with the synthetic 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone (III) that obtains of the Stigmasterol (II) that is easy to get, react under high chloro acid solution's catalysis with N-bromo ethanamide again and generate 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone (IV), then under illumination condition, react and generate 3 β-acetoxyl group-courage steroid-5 α-bromo-6 with lead tetraacetate, 19-epoxy-24-ketone (V), then use zinc powder/95% ethanol with 6, the 19-epoxy addition generates 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone (VI), then with performic oxidation 5, three-dimensional 3 β that obtain of the two keys of 6-single-mindedly, 5 α, 6 β, 19-tetrahydroxy-courage steroid-24-ketone (VII), by the Wittig reaction 24 carbonyls on the side chain are changed into methylene radical at last, obtain purpose product (formula I compound).Overall yield 9.3%.The process of reaction is shown below:
Figure A0311437000041
The concrete steps of the inventive method are as follows:
(1). with Stigmasterol (II) according to existent method (JianGuo Cui, LongMei Zeng, Jing Yu Su et al., Steroids, 2001,66,33-38) the synthetic 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone (III) that obtains;
(2). III is dissolved in the dioxane (consumption is generally and just dissolves III or many slightly), be chilled to 10~15 ℃, (common used concentration is 5%~10%wt to the high chloro acid solution of adding catalytic amount, consumption is 1%~5%mole) of III, lucifuge adds the N-bromo ethanamide of 1~1.4 times of weight in batches in 30~40 minutes, room temperature continued stirring reaction 30~40 minutes, add rare, cold sodium sulfite aqueous solution to reactant is tied to form white casse, dichloromethane extraction, removal of solvent under reduced pressure obtains a white solid, silica gel column chromatography, recrystallizing methanol obtain 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone (IV);
(3). the product IV in the previous step or white solid are dissolved in benzene/cyclohexane, and (volume ratio is 1/3~1/2, consumption is generally and just dissolves IV or many slightly) in the mixed solvent, the lead tetra-acetate that adds 5~10 times of weight, the iodine of 1~1.2 times of weight, the lime carbonate of 2~3 times of weight, illumination reaction is 5~7 hours under the protection of inert gas, the cooling back extracts respectively with sherwood oil and ethyl acetate, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, recrystallizing methanol obtains 3 β-acetoxyl group-courage steroid-5 α-bromo-6,19-epoxy-24-ketone (V);
(4). the product V in the previous step or light yellow solid be dissolved in 95% the ethanol (consumption is for just dissolving V or many slightly), the zinc powder that adds 3~5 times of weight, stirring and refluxing 5~7 hours, cooled and filtered is removed zinc powder, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, recrystallizing methanol obtain 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone (VI);
(5). the product VI in the previous step is dissolved in formic acid/tetrahydrofuran (THF), and (volume ratio is 1/2~1/1, consumption is generally and just dissolves VI or many slightly) in the mixed solvent, slowly drip the aqueous hydrogen peroxide solution (consumption is 2~5 times of weight of VI) of 30%v under the stirring at room, 40~45 ℃ were stirred 30~60 minutes, room temperature is placed and is spent the night, add the water stopped reaction, ethyl acetate extraction, removal of solvent under reduced pressure obtains a light yellow solid, adds the methanol solution (consumption of potassium hydroxide is 2~4 times of weight of VI) that contains 2~3%wt potassium hydroxide, reflux 10~15 minutes again, methyl alcohol is removed in the decompression of cooling back, solid ethyl acetate extraction, removal of solvent under reduced pressure obtain a light yellow solid, silica gel column chromatography, the methanol recrystallization obtains 3 β, 5 α, 6 β, 19-tetrahydroxy-courage steroid-24-ketone (VII);
(6). under protection of inert gas; anhydrous dimethyl sulfoxide solution (5mg/mL~10mg/mL) be heated to 70~80 ℃ to stir 35~45 minutes with sodium hydride; be cooled to the methyl triphenyl phosphonium iodide or the methyltriphenylphosphonium bromide (usually with a small amount of anhydrous dimethyl sulfoxide dissolving) that add 5~10 times of sodium hydride weight after the room temperature; stir after 10~15 minutes; product VII in the previous step of 0.5~1.0 times of sodium hydride weight of adding (usually with a small amount of anhydrous dimethyl sulfoxide dissolving); be warming up to 70~80 ℃ of stirring reactions 1~2 hour; add the frozen water stopped reaction after being cooled to room temperature; extracted with diethyl ether; removal of solvent under reduced pressure obtains a light yellow solid; silica gel column chromatography; the methanol recrystallization obtains purpose product 24-methylene radical-courage steroid-3 β; 5 α, 6 β, 19-tetrol (formula I compound).
The inventive method as starting raw material, obtains 24-methylene radical-courage steroid-3 β through the reaction of ten steps is synthetic first with the Stigmasterol (II) that is easy to get, 5 α, and 6 β, 19-tetrol (I), overall yield reaches 9.3%.
The present invention adopts unique reaction conditions and post-treating method, and in the process of synthetic 3 β of 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone (III)-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone (VI), the intermediate product of three-step reaction (IV and V) can not separate purification and be directly used in next step reaction, some unnecessary loss in the purification process have been avoided separating, can obtain higher relatively productive rate (improving about 3%), have actual production and be worth.
Embodiment
The invention will be further described by the following examples.
Embodiment 1:
(1). Stigmasterol is reacted synthetic obtain 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone, overall yield 63% according to the method for " JianGuo Cui, LongMei Zeng, JingYu Su et al., Steroids, 2001,66,33-38 " through five steps;
(2) .3 β-acetoxyl group-courage steroid-5-alkene-24-ketone 300mg is dissolved in the 3mL dioxane solution, after being cooled to 10 ℃ with ice-water bath, add 0.15mL high chloro acid solution (concentration is 7%wt), lucifuge adds 300mgN-bromo ethanamide, divide eight times and add, add in 40 minutes.Remove cryostat, room temperature continues to stir 40 minutes, adds rare cold sodium sulfite aqueous solution 20mL, and dichloromethane extraction four times merges organic phase, washes with water successively, and 5% sodium bicarbonate aqueous solution is washed, and saturated common salt is washed to neutrality, anhydrous sodium sulfate drying.Filter, removal of solvent under reduced pressure obtains a white solid, this solid is directly used in the next step, or separate with silica gel column chromatography (the petrol ether/ethyl acetate volume ratio is 5/1 wash-out), recrystallizing methanol obtains colourless acicular crystal 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone, fusing point: 128~130 ℃.
(3). the white solid 100mg that obtains in the step (2) is dissolved in the mixed solvent of 50mL benzene/cyclohexane (volume ratio is 1/3); add the 600mg lead tetraacetate fast; 120mg iodine, 250mg lime carbonate, under protection of inert gas with two 300 watts incandescent-lamp bulb illumination reflux 5 hours.Behind the cool to room temperature, filter, white filter residue washs with sherwood oil and ethyl acetate repeatedly, merging filtrate, and 5% sodium bicarbonate aqueous solution is washed secondary, and saturated common salt is washed to neutrality, anhydrous sodium sulfate drying.Filter, removal of solvent under reduced pressure obtains a light yellow solid, this solid is directly used in next step reaction, or separate with silica gel column chromatography (the petrol ether/ethyl acetate volume ratio is 7/1 wash-out), recrystallizing methanol obtains colourless acicular crystal 3 β-acetoxyl group-courage steroid-5 α-bromo-6,19-epoxy-24-ketone, fusing point: 139~141 ℃.
(4). the light yellow solid 100mg that obtains in the step (3) is dissolved in the 15mL ethanol (95%), add zinc powder 350mg, stirring and refluxing 5 hours, be cooled to the room temperature after-filtration, solid is washed repeatedly with ethanol, merges organic phase, and removal of solvent under reduced pressure obtains a light yellow solid, this solid obtains colourless acicular crystal 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone, fusing point: 132~133 ℃ with silica gel column chromatography (the petrol ether/ethyl acetate volume ratio is 5/1 wash-out) separation.Above three-step reaction overall yield is 41%.
(5) .3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone 100mg is dissolved in the mixed solvent of 3mL formic acid/tetrahydrofuran (THF) (volume ratio is 1/2), the aqueous hydrogen peroxide solution 0.3mL of dropping 30% under the stirring at room, heating and remain on 45 ℃ of half hours after, room temperature is placed and to be spent the night.Add the water stopped reaction, ethyl acetate extraction three times merges organic phase, washing once, 10% sodium bicarbonate aqueous solution is washed secondary, 5% aqueous sodium hydroxide washes once, saturated common salt is washed to neutrality, anhydrous sodium sulfate drying.Filter, obtain a light yellow solid after the removal of solvent under reduced pressure, in this solid, add 10mL methanol solution (containing 3%wt potassium hydroxide), reflux 15 minutes.Methyl alcohol is removed in the decompression of cooling back, the ethyl acetate dilution, and saturated common salt is washed to neutrality, anhydrous sodium sulfate drying.Filter, decompression is removed ethyl acetate and is obtained a light yellow solid, and silica gel column chromatography (benzene/acetone volume ratio is 1/1 wash-out) separates, the methanol recrystallization obtains colourless acicular crystal 3 β, 5 α, 6 β, 19-tetrahydroxy-courage steroid-24-ketone 44mg, fusing point: 213-214 ℃.Productive rate 45%.
(6). reaction flask cleans with argon gas earlier, under argon gas atmosphere, add sodium hydride (55%-65%) 50mg then,, add anhydrous dimethyl sulfoxide 4mL behind the decompressing and extracting sherwood oil with exsiccant sherwood oil (30-60 ℃) washing 3 times, 70~80 ℃ of stirring reactions 40 minutes, a yellow-green soln.The question response liquid cooling adds the methyl triphenyl phosphonium iodide 200mg that is dissolved in the 2mL methyl-sulphoxide to room temperature, solution becomes aureus, continue to stir after 10 minutes, add 3 β that are dissolved in the 1mL methyl-sulphoxide, 5 α, 6 β, 19-tetrahydroxy-courage steroid-24-ketone 15mg was 70~80 ℃ of stirring reactions 1 hour.After treating that temperature is reduced to room temperature, add 15mL cold water, with extracted with diethyl ether four times, diethyl ether solution washes with water to neutrality, boil off solvent, obtain a lurid solid, separate with silica gel column chromatography (benzene/acetone volume ratio is 1/1 wash-out), the methanol recrystallization obtains the purpose product 12mg of colourless needle-like crystalline form.Fusing point: 221~223 ℃.Productive rate 80%, the ten steps reaction overall yield initial from Stigmasterol is 9.3%.
Embodiment 2:
With reference to the method for embodiment 1, wherein:
The consumption of N-bromo ethanamide is 400mg in the step (2);
The consumption of lead tetraacetate is 900mg in the step (3), and the reaction times is 7 hours;
The consumption of zinc powder is 500mg in the step (4), and the reaction times is 7 hours;
The consumption of aqueous hydrogen peroxide solution is 0.5mL in the step (5), and the consumption of methanol solution (containing 3%wt potassium hydroxide) is 15mL;
The consumption of methyl triphenyl phosphonium iodide is 300mg in the step (6);
Other condition is identical with embodiment 1, is come to the same thing.
Embodiment 3:
With reference to the method for embodiment 1 and embodiment 2, wherein, step (6) replaces methyl triphenyl phosphonium iodide with the equivalent methyltriphenylphosphonium bromide respectively, and other condition is identical, is come to the same thing.
Purpose product (24-methylene radical-courage steroid-3 β, 5 α, 6 β, 19-tetrol) structural identification:
Fusing point: 221~223 ℃, bibliographical information is 224~226 ℃
Specific rotatory power: [α] 20 D=+3.5 ° of (c, 0.23, CH 3OH), bibliographical information is+2.6 ° of (c, 0.347, CH 3OH)
Ultimate analysis: C:74.86, H:10.86, C 28H 48O 4Calculated value: C:75.06, H:10.71
FAB-MS: M ++1=449
IR: 3315,1083,2942,2867,1640,1452,1378,1343,1080,1058,1030,879v/cm -1
1HNMR(DMSO-d 6):
0.662(s,3H,H-18),0.906(d,J=6.5Hz,3H,H-21),0.977(d,J=3.5Hz,3H,H-26),0.991(d,
J=3.5Hz,3H,H-27),2.198(m,J=6.5Hz,1H,H-25),3.273(m,1H,H-6),3.519(dd,J=12.0,
6.0Hz,1H,H-19a),3.731(s,1H,5-OH),3.839(m,1H,H-3),3.985(dd,J=12.0,3.5Hz,1H,
H-19b),4.155(d,J=5.5Hz,1H,3-OH),4.520(dd,J=6.0,3.5Hz,1H,19-OH),4.634(brs,1H,
H-28a),4.695(brs,1H,H-28b),5.041(d,J=5.5Hz,1H,6-OH)
13CNMR(DMSO-d 6):
155.72(C),106.38(CH 2),74.45(C),73.77(CH),65.76(CH),61.98(CH 2),56.49(CH),
55.52(CH),44.94(CH),42.55(C),42.46(C),40.97(CH 2),40.37(CH 2),35.13(CH),
34.15(CH 2),33.87(CH 2),33.00(CH),31.16(CH 2),30.78(CH),30.46(CH 2),27.78(CH 2),
26.82(CH 2),23.76(CH 2),21.71(CH 3),21.65(CH 2),21.56(CH 3),18.45(CH 3),12.15(CH 3)

Claims (4)

1. 24-methylene radical-courage steroid-3 β, 5 α, 6 β, the synthetic method of 19-tetrol, it is characterized in that the synthetic 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone III that obtains with Stigmasterol II, react under high chloro acid solution's catalysis with N-bromo ethanamide again and generate 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone IV, then generate 3 β-acetoxyl group-courage steroid-5 α-bromo-6 by the illumination annulation, 19-epoxy-24-ketone V, then epoxy addition generates 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone VI, then with performic oxidation 5, the two keys of 6-obtain 3 β, 5 α, 6 β, 19-tetrahydroxy-courage steroid-24-ketone VII changes into methylene radical with 24 carbonyls on the side chain at last, obtains purpose product I.
2. method according to claim 1 is characterized in that concrete steps are:
(1). with Stigmasterol II according to the synthetic 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone III that obtains of existent method;
(2). III is dissolved in the dioxane solution, be chilled to 10~15 ℃, the high chloro acid solution who adds catalytic amount, lucifuge adds the N-bromo ethanamide of 1~1.4 times of weight in batches in 30~40 minutes, and room temperature continued stirring reaction 30~40 minutes, the sodium sulfite aqueous solution stopped reaction, dichloromethane extraction, removal of solvent under reduced pressure obtains a white solid, silica gel column chromatography, and recrystallizing methanol obtains 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone IV;
(3). product IV in the previous step or white solid are dissolved in the mixed solvent of benzene/cyclohexane=1/3~1/2 volume ratio, the lead tetra-acetate that adds 5~10 times of weight, the iodine of 1~1.2 times of weight, the lime carbonate of 2~3 times of weight, illumination reaction is 5~7 hours under the protection of inert gas, cooling back sherwood oil and ethyl acetate extraction, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, recrystallizing methanol obtain 3 β-acetoxyl group-courage steroid-5 α-bromo-6,19-epoxy-24-ketone V;
(4). the product V in the previous step or light yellow solid be dissolved in 95% the ethanolic soln, the zinc powder that adds 3~5 times of weight, stirring and refluxing 5~7 hours, cooled and filtered, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, recrystallizing methanol obtain 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone VI;
(5). the product VI in the previous step is dissolved in the mixed solvent of formic acid/tetrahydrofuran (THF)=1/2~1/1 volume ratio, slowly drips the aqueous hydrogen peroxide solution of 30%v under the stirring at room, consumption is 2~5 times of VI weight; 40~45 ℃ were stirred 3060 minutes, and room temperature is placed and spent the night, and adds the water stopped reaction, ethyl acetate extraction, and removal of solvent under reduced pressure obtains a light yellow solid, adds the methanol solution that contains 2~3%wt potassium hydroxide again, and the consumption of potassium hydroxide is 2~4 times of VI weight; Reflux 10~15 minutes, methyl alcohol is removed in the decompression of cooling back, ethyl acetate extraction, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, the methanol recrystallization obtains 3 β, 5 α, 6 β, 19-tetrahydroxy-courage steroid-24-ketone VII;
(6). under protection of inert gas; the anhydrous dimethyl sulfoxide solution of 5mg/mL~10mg/mL sodium hydride is heated to 70~80 ℃ of stirrings 35~45 minutes; be cooled to the methyl triphenyl phosphonium iodide or the methyltriphenylphosphonium bromide that add 5~8 times of sodium hydride weight after the room temperature; stir after 10~15 minutes; product VII in the previous step of 0.5~1.0 times of sodium hydride weight of adding; be warming up to 70~80 ℃ of stirring reactions 1~2 hour; add the frozen water stopped reaction after being cooled to room temperature; extracted with diethyl ether, removal of solvent under reduced pressure obtain a light yellow solid, silica gel column chromatography; the methanol recrystallization obtains purpose product 24-methylene radical-courage steroid-3 β; 5 α, 6 β, 19-tetrol.
3. method according to claim 2, the concentration that it is characterized in that used high chloro acid solution in the step (2) is 5%~10%wt, consumption is 1%~5%mole of III.
4. according to claim 2 or 3 described methods, it is characterized in that methyl triphenyl phosphonium iodide used in the step (6) or methyltriphenylphosphonium bromide and VII, respectively with adding again after the anhydrous dimethyl sulfoxide dissolving.
CN 03114370 2003-05-06 2003-05-06 Synthetic method of 24-methylene-cholesterol-3 beta, 5 alpha, 6 beta,19-tetraalcohol Pending CN1448400A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007076655A1 (en) * 2005-12-31 2007-07-12 Sun Yat-Sen University METHOD FOR SYNTHESIS OF CHOLEST-3β,5α,6β,19-TETRAHYDROXY-24-ONE AND ITS DERIVATIVES
WO2008017216A1 (en) * 2006-08-03 2008-02-14 Sun Yat -Sen University The application of marine steroid in preparing the medicine of treating neurons damaging
CN101560236B (en) * 2009-05-22 2011-07-06 中山大学 Method for synthesizing marine polyhydroxyl sterol (25R)-5alpha -cholest-3 beta, 5alpha, 6beta, 26-tetrol
CN104497086A (en) * 2014-12-12 2015-04-08 中山大学 Androstane-3beta, 5alpha, 6beta,19-tetraol as well as preparation method and application thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007076655A1 (en) * 2005-12-31 2007-07-12 Sun Yat-Sen University METHOD FOR SYNTHESIS OF CHOLEST-3β,5α,6β,19-TETRAHYDROXY-24-ONE AND ITS DERIVATIVES
CN100436474C (en) * 2005-12-31 2008-11-26 中山大学 Process for synthesizing cholester-3 bata, 5 alpha, 6 bata, 19-tetrahydroxy-24-one and derivative
WO2008017216A1 (en) * 2006-08-03 2008-02-14 Sun Yat -Sen University The application of marine steroid in preparing the medicine of treating neurons damaging
CN101560236B (en) * 2009-05-22 2011-07-06 中山大学 Method for synthesizing marine polyhydroxyl sterol (25R)-5alpha -cholest-3 beta, 5alpha, 6beta, 26-tetrol
CN104497086A (en) * 2014-12-12 2015-04-08 中山大学 Androstane-3beta, 5alpha, 6beta,19-tetraol as well as preparation method and application thereof

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