CN1448399A - Synthetic method of 24-methylene-cholesterol-5-alkenyl-3 beta, 19-glycol - Google Patents

Synthetic method of 24-methylene-cholesterol-5-alkenyl-3 beta, 19-glycol Download PDF

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CN1448399A
CN1448399A CN 03114287 CN03114287A CN1448399A CN 1448399 A CN1448399 A CN 1448399A CN 03114287 CN03114287 CN 03114287 CN 03114287 A CN03114287 A CN 03114287A CN 1448399 A CN1448399 A CN 1448399A
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ketone
courage steroid
alkene
acetoxyl group
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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-5-ene-3beta,19-diol (Litoserol) 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; hydrolysis to produce 3beta, 19-dihydroxy-cholest5-ene-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-5-alkene-3 β, the synthetic method of 19-glycol
Technical field
The present invention relates to have natural product 24-methylene radical-courage steroid-5-alkene-3 β of remarkable physiologically active, 19-glycol (24-methylene-cholest-5-en-3 β, 19-diol; Litosterol) artificial synthesis.
Background technology
24-methylene radical-courage steroid-5-alkene-3 β, (structure is suc as formula shown in the I for the 19-glycol, hereinafter to be referred as formula I compound) at first be that people such as Kazuo IGUCHI separate from the soft coral Litophyton viridis of ocean and obtain (Kazuo IGUCHI, Shuichi SAITOH, Yasuji YAMADA, Chem.Pharm.Bull., 1989,37,2553-2554), 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 1.76,1.31,1.10 and 0.45 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 has a significant anti-mycotic activity (MICs can suppress the growth of 90% H37Rv pulmonary tuberculosis cell when being 3.13 μ g/mL), simultaneously because its toxicity is low, be an ideal drug candidate (Khalid A.El Sayed, Piotr Bartyzel, Xiaoyu Shen, et al., Tetrahedron, 2000,56,949-953).
Figure A0311428700031
24-methylene radical-courage steroid-5-alkene-3 β, the content of 19-glycol in marine organisms is atomic, Kazuo IGUCHI etc. is divided into from 6.5kg soft coral Litophyton viridis from obtaining this compound of 18mg, and the halobiontic quantity of this kind is few, 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-5-alkene-3 β, the method for 19-glycol.
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 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 hydrolysis generates 3 β, 19-dihydroxyl-courage steroid-5-alkene-24-ketone (VII), at last 24 carbonyls on the side chain are changed into methylene radical, obtain purpose product (formula I compound).Overall yield 14%.The process of reaction is shown below:
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 ℃, (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 the sodium sulfite aqueous solution stopped reaction, 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, 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 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 (general 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). product VI in the previous step or light yellow solid are dissolved in the tetrahydrofuran (THF) (general consumption is for just dissolving VI or many slightly), adding concentration is the potassium hydroxide methanol solution (consumption of potassium hydroxide is 1~3 times of VI weight) of 2~3%wt, reflux 10~15 minutes, cooling back removal of solvent under reduced pressure, ethyl acetate extraction, removal of solvent under reduced pressure obtain a light yellow solid, silica gel column chromatography, recrystallizing methanol obtains 3 β, 19-dihydroxyl-courage steroid-5-alkene-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 5~8 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 (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; recrystallizing methanol obtains purpose product 24-methylene radical-courage steroid-5-alkene-3 β, 19-glycol (formula I compound).
The inventive method as starting raw material, obtains 24-methylene radical-courage steroid-5-alkene-3 β through the reaction of ten steps is synthetic first with the Stigmasterol (II) that is easy to get, 19-glycol (I), and overall yield reaches 14%.
The inventive method is at synthetic 3 β of 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone (III), adopt unique reaction conditions and post-treating method in the process of 19-dihydroxyl-courage steroid-5-alkene-24-ketone (VII), intermediate product (the IV of four-step reaction, V, VI) can not separate purification and be directly used in next step reaction, avoided separating some unnecessary loss in the purification process, can obtain higher relatively productive rate (improving 4%), such treatment process has more actual production and is 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, Jing Yu 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 300mg N-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 ethanolic soln of 15mL95%, add zinc powder 350mg, stirring and refluxing 5 hours, be cooled to the room temperature after-filtration, solid is washed repeatedly with ethanol, merge organic phase, 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 5/1 wash-out), recrystallizing methanol obtains colourless acicular crystal 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone, fusing point: 132~133 ℃.
(5). the light yellow solid 100mg that obtains in the step (4) is dissolved in the 20mL tetrahydrofuran solution, adds 6mL methanol solution (containing 3%wt potassium hydroxide), reflux 15 minutes.Be cooled to room temperature, removal of solvent under reduced pressure obtains a yellow solid, the ethyl acetate dilution, and saturated common salt is washed to neutrality, anhydrous sodium sulfate drying.Filter, removal of solvent under reduced pressure, the light yellow solid that obtains separates with silica gel column chromatography (sherwood oil/acetone volume ratio is 4/1 wash-out), and recrystallizing methanol obtains colourless acicular crystal 3 β, 19-dihydroxyl-courage steroid-5-alkene-24-ketone 74mg, fusing point: 155~156 ℃.Above four-step reaction overall yield is 29%.
(6). reaction flask cleans with argon gas earlier, under argon gas atmosphere, add sodium hydride (55%-65%) 80mg then,, add anhydrous dimethyl sulfoxide 5mL 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.After question response liquid is reduced to room temperature, add the methyl triphenyl phosphonium iodide 400mg that is dissolved in the 3mL methyl-sulphoxide, solution becomes aureus, continue to stir after 10 minutes, add 3 β be dissolved in the 1mL methyl-sulphoxide, 19-dihydroxyl-courage steroid-5-alkene-24-ketone 25mg 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, the lurid solid that obtains, the latter separates with silica gel column chromatography (sherwood oil/acetone volume ratio is 3/1 wash-out), and recrystallizing methanol obtains the purpose product 18mg of colourless needle-like crystalline form.Fusing point: 166~167 ℃.Productive rate 74%, the ten steps reaction overall yield initial from Stigmasterol is 14%.
Embodiment 2:
With reference to the method for implementing 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 methanol solution (containing 3%wt potassium hydroxide) is 10mL in the step (5);
The consumption of methyl triphenyl phosphonium iodide is 600mg in the step (6);
Other condition is identical with enforcement 1, is come to the same thing.
Embodiment 3:
With reference to the method for enforcement 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-5-alkene-3 β, 19-glycol) structural identification:
Fusing point: 166~167 ℃, bibliographical information is 165~166 ℃
Specific rotatory power: [α] 20 D=-24 ° of (c, 0.125, CHCl 3), bibliographical information is-25.8 ° of (c, 0.24, CHCl 3)
Ultimate analysis: C:79.95, H:11.23, C 28H 46O 2Calculated value: C:81.10, H:11.18
FAB-MS: M ++1=415
IR: 3394,3082,2957,2936,2869,1642,1466,1378,1054,964,888v/cm -1
1HNMR(CDCl 3):?0.737(s,3H,18-CH 3),0.947(d,J=6.5Hz,3H,H-21),1.014(d,J=2.5Hz,3H,H-26),
1.028(d,J=2.5Hz,3H,H-27),3.573(m,1H,H-3),3.610(d,J=11.5Hz,1H,H-19a),
3.821(d,J=11.5Hz,1H,H-19b),4.652(brs,1H,H-28a),4.711(brs,1H,H-28b),
5.747(brd,J=5.0Hz,1H,H-6)
13CNMR(CDCl 3):156.88(C),135.56(C),127.40(CH),105.94(CH 2),71.38(CH),62.75(CH 2),
57.68(CH),56.00(CH),50.41(CH),42.59(C),42.35(CH 2),41.55(C),40.07(CH 2),
35.76(CH),34.71(CH 2),33.82(CH),33.44(CH),33.36(CH 2),32.00(CH 2),
31.25(CH 2),31.01(CH 2),28.22(CH 2),24.08(CH 2),22.00(CH 3),21.87(CH 3),
21.81(CH 2),18.70(CH 3),12.22(CH 3)

Claims (4)

1. 24-methylene radical-courage steroid-5-alkene-3 β, the synthetic method of 19-glycol, it is characterized in that with the synthetic 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone that obtains of Stigmasterol, 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, then generate 3 β-acetoxyl group-courage steroid-5 α-bromo-6 by the illumination annulation, 19-epoxy-24-ketone, then epoxy addition generates 3 β-acetoxyl group-courage steroid-5-alkene-19-hydroxyl-24-ketone, then hydrolysis generates 3 β, 19-dihydroxyl-courage steroid-5-alkene-24-ketone, at last 24 carbonyls on the side chain are changed into methylene radical, obtain the purpose product.
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). product VI in the previous step or light yellow solid are dissolved in the tetrahydrofuran solution, and adding concentration is the potassium hydroxide methanol solution of 2~3%wt, and the consumption of potassium hydroxide is 1~3 times of VI weight; Reflux 10~15 minutes, cooling back removal of solvent under reduced pressure, ethyl acetate extraction, removal of solvent under reduced pressure obtains a light yellow solid, silica gel column chromatography, recrystallizing methanol obtains 3 β, 19-dihydroxyl-courage steroid-5-alkene-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 obtains a light yellow solid; silica gel column chromatography, recrystallizing methanol obtain purpose product 24-methylene radical-courage steroid-5-alkene-3 β, 19-glycol.
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 or methyltriphenylphosphonium bromide used in the step (6), and VII, respectively with adding again after the anhydrous dimethyl sulfoxide dissolving.
CN 03114287 2003-04-24 2003-04-24 Synthetic method of 24-methylene-cholesterol-5-alkenyl-3 beta, 19-glycol Pending CN1448399A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007076656A1 (en) * 2005-12-31 2007-07-12 Sun Yat-Sen University METHOD FOR SYNTHESIS OF CHOLEST-5-EN-3β,19-DIHYDROXY-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
CN100436475C (en) * 2005-12-31 2008-11-26 中山大学 Process for synthesizing cholester-5-ylene-3bata-hydroxy-24-one and derivative

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007076656A1 (en) * 2005-12-31 2007-07-12 Sun Yat-Sen University METHOD FOR SYNTHESIS OF CHOLEST-5-EN-3β,19-DIHYDROXY-24-ONE AND ITS DERIVATIVES
CN100410270C (en) * 2005-12-31 2008-08-13 中山大学 Synthesis method of cholesterol-5-olefin-3 beta,19-dihydroxy-24-ketone and derivative
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
CN100436475C (en) * 2005-12-31 2008-11-26 中山大学 Process for synthesizing cholester-5-ylene-3bata-hydroxy-24-one and derivative

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