CN1793159A - Process for synthesizing cholester-3 bata, 5 alpha, 6 bata, 19-tetrahydroxy-24-one and derivative - Google Patents
Process for synthesizing cholester-3 bata, 5 alpha, 6 bata, 19-tetrahydroxy-24-one and derivative Download PDFInfo
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Abstract
The invention discloses a cholest -3beta, 5alpha, 6beta, 19-4-hydroxy-24-ketone and the ramification compounding method that uses hyodeoxycholic acid as raw material to make 3beta-acetoxy-cholest -5-alkene-24-acid that would react with protochloride to form cholest acyl chloride, which would react with isopropyl cadion under the radiation of ultrasonic to form 3beta-acetoxy-cholest-5-alkene-24-ketone, and taking reaction with N-bromization succimide/ perchloric acid water solution reaction system to gain 3beta-acetoxy-cholest-5alpha-bromine-6beta-hydroxy-24- ketone, using diacetyl oxygen iodobenzene to form 3beta-acetoxy-cholest-5alpha- bromine-6beta, 19-epoxy-24-ketone, using zinc powder/glacial acetic acid system to deoxidizing 3beta, 19-diacetoxy-cholest-5-alkene-24-ketone; using oxidant to oxidizing 5, 6 double bond, taking hydrolysis reaction to gain cholest -3beta, 5alpha, 6beta, 19-4-hydroxy-24-ketone, finally taking reaction with methyl triphenyl bromination phosphine to form 24-methylene-cholest -3beta, 5alpha, 6beta, 19-4-alcohol, taking reaction with hydrazine to form cholest -3beta, 5alpha, 6beta, 19-4-hydroxy-24-ketone. The invention is low cost, high yield. And the target compound has obvious protection function to neurone dead cell induced by low potassium.
Description
Technical field
The present invention relates to courage steroid-3 β, 5 α, 6 β, the synthetic method of 19-tetrahydroxy-24-ketone (structure such as I) and derivative.
Background technology
24-methylene radical-courage steroid-3 β; 5 α; 6 β; 19-tetrol (structure is suc as formula II) is to separate a kind of poly-hydroxy steroidal compounds obtain (Wang Guiyang, Li Fengying, once Gansu Province plum etc. from South Sea soft coral Nephthea albida and N.tiexieralv erseveldt; SCI; 1992,13,623-627).This compound all has stronger kill capability (Chang-Yih Duh, Shang-Kwei, Mei-Jen Chu et al. to human body rectum cancer cell, human body lung carcinoma cell, muroid lymphocytic cancer cell; J.Nat.Prod., 1998,61; 1022-1024), multiple inflammation there are significant anti-inflammatory action (Wang Zhenglian, Xu Shibo; Liu Qing etc.; ocean, the torrid zone, 1999,18; 27-32), this compound has significant provide protection to low potassium inductive Neuron Apoptosis cell.
The content of this compound in marine organisms is extremely low, directly extracts with the marine organisms raw material to remain at present in a lot of problems, and synthetic this compound of research has very high pharmaceutical use.Intermediate courage steroid-3 β of synthetic this compound, 5 α, 6 β, 19-tetrahydroxy-24-ketone and nitrogen containing derivative have significant provide protection to low potassium inductive Neuron Apoptosis cell.
Summary of the invention
The purpose of this invention is to provide a kind of courage steroid-3 β, 5 α, 6 β, the synthetic method of 19-tetrahydroxy-24-ketone and derivative.
Synthetic method of the present invention is raw material with the Hyodeoxycholic Acid, prepare 3 β-acetoxyl group-courage steroid-5-alkene-24-acid by become courage steroid acyl chlorides with the sulfur oxychloride prepared in reaction, the ultrasonic wave radiation down and the sec.-propyl cadion react 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone, again with N-bromo-succinimide/high chloro acid solution's system in reaction obtain 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone, the oxidation of diacetoxy phenyl-iodide is closed ring and is generated 3 β-acetoxyl group-courage steroid-5 α-bromo-6,19-epoxy-24-ketone, then generate 3 β with zinc powder/Glacial acetic acid system or zinc powder/pure reduction system, 19-diacetoxy-courage steroid-5-alkene-24-ketone, get courage steroid-5-alkene-3 β, 19-hydroxyl-24-ketone by alkaline hydrolysis again; Get courage steroid-3 β with oxygenant oxidation, hydrolysis reaction, 5 α, 6 β, 19-tetrahydroxy-24-ketone; With methyltriphenylphosphonium bromide reaction Synthetic 2 4-methylene radical-courage steroid-3 β, 5 α, 6 β, 19-tetrol; With synthetic courage steroid-3 β of hydrazine reaction, 5 α, 6 β, the two hydrazones of 19-tetrahydroxy-24-.Reaction scheme is as shown below:
I. courage steroid-3 β, 5 α, 6 β, 19-tetrahydroxy-24-ketone;
II.24-methylene radical-courage steroid-3 β, 5 α, 6 β, 19-tetrol;
III. courage steroid-3 β, 5 α, 6 β, the two hydrazones of 19-tetrahydroxy-24-;
IV.3 β-acetoxyl group-courage steroid-5-alkene-24-acid;
V.3 β-acetoxyl group-courage steroid-5-alkene-24-ketone;
VI.3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone;
VII.3 β-acetoxyl group-courage steroid-5 α-bromo-6 β, 19-epoxy-24-ketone;
VIII.3 β, 19-diacetoxy-courage steroid-5-alkene-24-ketone;
IXa.3 β, 19-diacetoxy-courage steroid-5,6 beta epoxides-24-ketone;
IXb.3 β, 19-diacetoxy-courage steroid-5,6 α-epoxy-24-ketone;
X.3 β, 19-diacetoxy-courage steroid-5,6-dihydroxyl-24-ketone.
The concrete steps of synthetic method of the present invention are:
(1) the IV reference literature (Bharucha KR, Buckley GC, Cross CK, et al.Can J Chem., 1955,34:982-990.) synthetic;
(2) IV is dissolved in dry-out benzene and adds sulfur oxychloride, add the pyridine of catalytic amount, at room temperature stirred 2～4 hours, be evaporated to driedly, add benzene again and continue to concentrate, take residual sulfur oxychloride out of, yellow heavy-gravity liquid;
(3) take by weighing dry magnesium powder, add anhydrous diethyl ether, drip different N-PROPYLE BROMIDE/anhydrous ether solution, add back ultrasonic radiation 15～30 minutes, add Cadmium chloride fine powder after the cooling in batches, stirring under the ultrasonic wave radiation under 25～40 ℃, the ice bath cooling down, slowly be added drop-wise to 30～40% dry-out benzene solution of product of last step in the reaction system, drip off the back and continue ultrasonic wave radiation backflow 1～2 hour, after the ice bath cooling, drip 1: 1 aqueous hydrochloric acid, extract with benzene, the benzene layer is washed till neutrality with distilled water, drying, concentrating under reduced pressure, silica gel column chromatography gets white solid V;
(4) extracting waste solid V adds organic solvent dissolution, adds HClO again
4And water, under the lucifuge condition, adding the N-succimide then in batches, controlled temperature is lower than 10 ℃, reacts 1～2 hour down at 15～20 ℃ afterwards, adds 10%Na in reaction solution
2S
2O
8The aqueous solution, after the layering, the upper strata concentrates, the CH of lower floor
2Cl
2Extraction merges organic layer, uses saturated NaHCO
3Solution washing is washed with distilled water to neutrality again, drying, and concentrating under reduced pressure, silica gel column chromatography gets white solid VI;
(5) get compound VI, dissolve in hexanaphthene/benzene mixed solution, add oxygenant, under 20～40 ℃ of stirrings, ultra violet lamp 7～8 hours, reaction solution is used 10% sodium thiosulfate solution successively, saturated NaHCO
3Solution and distilled water wash are extremely neutral, drying, and concentrating under reduced pressure gets light yellow compound VI I;
(6) get compound VIII and add the Glacial acetic acid dissolving, add zinc powder, stirring and refluxing 20～24 hours; Suction filtration while hot, filtrate is used dichloromethane extraction, extraction liquid is washed till neutrality with saturated sodium bicarbonate solution and distilled water respectively, drying, concentrating under reduced pressure, silica gel column chromatography, light yellow thick liquid VIII;
(7) get compound VIII and add the methylene dichloride dissolving, add oxygenant, stir under the room temperature, methylene dichloride is removed in decompression, the clinker acetic acid ethyl dissolution adds the washing of 10% sodium sulfite solution then to colourless, is washed to neutrality, drying, concentrating under reduced pressure gets white solid IXa, it is added acetone solution, add perchloric acid, stir under the room temperature, transfer pH to neutral, pressure reducing and steaming acetone is used dichloromethane extraction, drying, concentrating under reduced pressure gets white solid X;
(8) get compound VIII and add the dissolving of 88% formic acid, boiling water bath heating 5 minutes is cooled to room temperature, adds oxygenant, room temperature was placed 24 hours, behind the dilute with water, use ethyl acetate extraction, add the washing of 10% sodium sulfite solution then to colourless, be washed to neutrality, drying, concentrating under reduced pressure gets white solid IXb;
(9) will go up step product IXb or X is dissolved in the methyl alcohol, adding concentration is 3% potassium hydroxide alcoholic solution, reflux 15～30 minutes, it is neutral transferring pH, methyl alcohol is removed in underpressure distillation, ethyl acetate extraction, the organic layer drying, the pressure reducing and steaming solvent gets light yellow solid, silica gel column chromatography gets white solid I;
(10) methyltriphenylphosphonium bromide is added in the anhydrous tetrahydrofuran solution, inject n-Butyl Lithium, injection rate just is dissolved as suitable with methyltriphenylphosphonium bromide, stirring reaction is 4～6 hours under the room temperature, I in the last step is added reaction system, continue reaction 2～3 hours, reaction solution is poured into rapidly in the saturated ammonium chloride solution, use extracted with diethyl ether, ether layer drying, the pressure reducing and steaming solvent gets light yellow solid, silica gel column chromatography gets white solid II;
(11) I is added dissolve with ethanol, add in the aqueous solution of hydrazine, separate thermal backflow, the pressure reducing and steaming solvent adds entry, and it is neutral transferring pH, and ethyl acetate extraction gets white solid, and silica gel column chromatography gets white solid III.
In the above-mentioned reactions steps, the concentration of the benzole soln of II is 25～45% in the step (2), and the amount of sulfur oxychloride is 1.0～2.0 times of mole number of II; The amount of magnesium powder is 1.2～3.0 times of mole number of II in the step (3); Organic solvent in the step (4) is tetrahydrofuran (THF) or dioxane; Oxygenant in the step (5) is diacetoxy phenyl-iodide or lead tetra-acetate; Oxygenant in the step (7) is potassium permanganate/copper sulfate or metachloroperbenzoic acid; Oxygenant in the step (8) is 30% hydrogen peroxide.
The reaction scheme of synthetic method of the present invention is scientific and reasonable, the productive rate height of synthetics, synthetic intermediate courage steroid-3 β, 5 α, 6 β, 19-tetrahydroxy-24-ketone, 24-methylene radical-courage steroid-3 β, 5 α, 6 β, 19-tetrol; And courage steroid-3 β, 5 α, 6 β, the two hydrazones of 19-tetrahydroxy-24-transfer the cell of dying to have significant provide protection to low potassium inductive neurone.
Embodiment
Following examples are in order to explanation the present invention, but protection scope of the present invention is not only for following examples.Unless otherwise specified, in following examples: I represents courage steroid-3 β, 5 α, 6 β, 19-tetrahydroxy-24-ketone; II represents 24-methylene radical-courage steroid-3 β, 5 α, 6 β, 19-tetrol; III represents courage steroid-3 β, 5 α, 6 β, the two hydrazones of 19-tetrahydroxy-24-; IV represents 3 β-acetoxyl group-courage steroid-5-alkene-24-acid; V represents 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone; VI represents 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone; VII represents 3 β-acetoxyl group-courage steroid-5 α-bromo-6 β, 19-epoxy-24-ketone; VIII represents 3 β, 19-diacetoxy-courage steroid-5-alkene-24-ketone; IXa represents 3 β, 19-diacetoxy-courage steroid-5,6 beta epoxides-24-ketone; IXb represents 3 β, 19-diacetoxy-courage steroid-5,6 α-epoxy-24-ketone; X represents 3 β, 19-diacetoxy-courage steroid-5,6-dihydroxyl-24-ketone.
Embodiment 1
Courage steroid-3 β, 5 α, 6 β, 19-tetrahydroxy-24-ketone synthetic
(1) get compound (V) 100 gram, add 300ml benzene, the 20ml sulfur oxychloride, the 1ml pyridine at room temperature stirred 2 hours, was evaporated to driedly, removed residual sulfur oxychloride, chloride compounds with the dissolving of 200ml benzene, standby.Get 20 gram exsiccant magnesium powder, add the 60ml anhydrous diethyl ether, the anhydrous ether solution of the different N-PROPYLE BROMIDE of instillation 73ml under 60% ultrasonic wave radiation adds and continued ultrasonic 15～30 minutes, add 78 gram Cadmium chloride fine powdeies after the cooling in four batches, under 25～40 ℃, opened for 60% ultra-sonic oscillation half an hour.The frozen water cooling slowly drips the benzole soln of acyl chlorides down, drips the ultrasonic backflow of Bi Jixu 2 hours.After water-cooled on the rocks is frozen 30 minutes, drip 150ml (1: 1) aqueous hydrochloric acid, with benzene extraction three times, the benzene layer is washed till neutrality with distilled water, anhydrous sodium sulfate drying, and concentrating under reduced pressure, silica gel column chromatography gets white solid (VI).
(2) extracting waste solid (VI) 20 grams add the dissolving of 20mL tetrahydrofuran (THF), add an amount of HClO
4And water, joining in the reaction solution at lucifuge condition decline 20 gram N-succimides then in batches, controlled temperature is lower than 10 ℃, reacts 2 hours down at 15～20 ℃ afterwards.In reaction solution, add 10%Na
2S
2O
8The aqueous solution after the layering, is used CH
2Cl
2Extraction merges organic layer, uses saturated NaHCO
3Solution washing is washed with distilled water to neutrality again, anhydrous sodium sulfate drying, and concentrating under reduced pressure, silica gel column chromatography gets white solid (VII).
(3) get compound (VII) 5 gram, dissolve in 1000mL hexanaphthene/benzene mixed solution, add 4 gram diacetoxy phenyl-iodides, 2.8 gram iodine stir down, 40 ℃ of following ultra violet lamps 2 hours, and reaction solution is used 10% sodium thiosulfate solution successively, saturated NaHCO
3Solution and distilled water wash are to neutral, and anhydrous sodium sulfate drying, concentrating under reduced pressure get light yellow thick compound (VIII).
(4) getting 2 gram compounds (VIII) add the dissolving of 40 Glacial acetic acid, add 6 zinc powders, stirring and refluxing 20～24 hours.Suction filtration while hot, filtrate is used dichloromethane extraction to going in 5 times of water gagings, extraction liquid is washed till neutrality with saturated sodium bicarbonate solution and distilled water respectively, anhydrous sodium sulfate drying, concentrating under reduced pressure, silica gel column chromatography, light yellow thick liquid (III).
(5) get compound (VIII) and add methylene dichloride dissolving (concentration is about 2.5～10%), add cupric sulfate crystals and potassium permanganate mix powder, add an amount of trimethyl carbinol and water again, stirred 2 hours under the room temperature.Methylene dichloride is removed in decompression, and the clinker acetic acid ethyl dissolution adds the washing of 10% sodium sulfite solution then to colourless, is washed to neutrality, anhydrous sodium sulfate drying, and concentrating under reduced pressure gets white solid (IXa).With its adding acetone solution, add an amount of perchloric acid, stirred 24 hours under the room temperature, transfer pH to neutral with saturated sodium bicarbonate solution, pressure reducing and steaming acetone is used dichloromethane extraction, anhydrous sodium sulfate drying, concentrating under reduced pressure gets white solid (X).
(6) will go up the potassium hydroxide methanol solution that step product (X) 1g is added to 500mL3%, reflux 30 minutes, pH with 5% hydrochloride adjusted solution is neutral, methyl alcohol is removed in underpressure distillation, and ethyl acetate extraction three times, organic layer merge uses anhydrous sodium sulfate drying, the pressure reducing and steaming solvent, get light yellow solid, silica gel column chromatography gets white solid (I).
Embodiment 2
Courage steroid-3 β, 5 α, 6 β, 19-tetrahydroxy-24-ketone synthetic
(1)～(4) identical with step (1)～(4) of embodiment 1.
(5) get compound (VIII) and add methylene dichloride dissolving (concentration is about 2.5～10%), add metachloroperbenzoic acid, stirred 2 hours under the room temperature.Methylene dichloride is removed in decompression, and the clinker acetic acid ethyl dissolution adds the washing of 10% sodium sulfite solution then to colourless, is washed to neutrality, anhydrous sodium sulfate drying, and concentrating under reduced pressure gets white solid (IXa).With its adding acetone solution, add an amount of perchloric acid, stirred 24 hours under the room temperature, transfer pH to neutral with saturated sodium bicarbonate solution, pressure reducing and steaming acetone is used dichloromethane extraction, anhydrous sodium sulfate drying, concentrating under reduced pressure gets white solid (X).
(6) identical with the step (6) of implementing 1.
Embodiment 3
Courage steroid-3 β, 5 α, 6 β, 19-tetrahydroxy-24-ketone synthetic
(1)～(4) identical with step (1)～(4) of embodiment 1.
(5) get compound (VIII) and add 88% formic acid dissolving (concentration is about 5%), boiling water bath heating 5 minutes is cooled to room temperature, adds 30% superoxol, room temperature was placed 24 hours, behind the dilute with water, use ethyl acetate extraction, add the washing of 10% sodium sulfite solution then to colourless, be washed to neutrality, anhydrous sodium sulfate drying, concentrating under reduced pressure gets white solid (IXb).
(6) will go up the potassium hydroxide methanol solution that step product (IXb) 1g is added to 500L3%, reflux 30 minutes, pH with 5% hydrochloride adjusted solution is neutral, methyl alcohol is removed in underpressure distillation, and ethyl acetate extraction three times, organic layer merge uses anhydrous sodium sulfate drying, the pressure reducing and steaming solvent, get light yellow solid, silica gel column chromatography gets white solid (I).
Embodiment 4
24-methylene radical-courage steroid-3 β, 5 α, 6 β, 19-tetrol synthetic
(1)～(6) identical with step (1)～(6) of embodiment 1.
(7) add 2 gram methyltriphenylphosphonium bromides in the 50mL anhydrous tetrahydrofuran solution, logical nitrogen injects an amount of n-Butyl Lithium, stirring reaction is 6 hours under the room temperature, the tetrahydrofuran solution of 1 gram (I) is injected reaction system, continue reaction 2 hours, reaction solution is poured into rapidly in the saturated ammonium chloride solution, use extracted with diethyl ether, ether layer anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets light yellow solid, silica gel column chromatography gets white solid (II).
Embodiment 5
Courage steroid-3 β, 5 α, 6 β, the two hydrazones of 19-tetrahydroxy-24-synthetic
(1)～(6) identical with step (1)～(6) of embodiment 1.
(7) restrain (I) with 1 and use the 10mL dissolve with ethanol, the aqueous solution of adding 1mL50% hydrazine, reflux 4 hours, the pressure reducing and steaming solvent adds suitable quantity of water, and it is neutral transferring pH, and ethyl acetate extraction gets white solid, and silica gel column chromatography gets white solid (III).
Embodiment 6
Courage steroid-3 β, 5 α, 6 β, the two hydrazones of 19-tetrahydroxy-24-synthetic
(1)～(6) identical with step (1)～(6) of embodiment 1.
(7) restrain (I) with 1 and use the 20mL dissolve with ethanol, the aqueous solution of adding 1mL80% hydrazine, reflux 2 hours, the pressure reducing and steaming solvent adds suitable quantity of water, and it is neutral transferring pH, and ethyl acetate extraction gets white solid, and silica gel column chromatography gets white solid (III).
Purpose product 1: courage steroid-3 β, 5 α, 6 β, the structural identification of 19-tetrahydroxy-24-ketone
Fusing point: 213-214 ℃
Ultimate analysis: C
27H
46O
5Measured value: C, 71.60; H, 20.50; Theoretical value: C, 71.92; H, 10.29,
MS：[M+Na]
+＝473
IR：3324，2941，2889，1708，1464，1380，1342，1048，975.
1HNMR(DMSO)：
3.99(1H，d，19-CH)，3.86(m，1H，3β-CH)，3.52(1H，m，19-CH)，3.23(m，1H，6β-CH)，2.59(1H，m，25-CH)，1.18(3H，d，26-CH
3，27-CH
3)，1.01(3H，s，19-CH
3)，0.87(3H，d，21-CH
3)，0.65(3H，s，18-CH
3).
13CNMR(DMSO)：
214.2(C)，74.5(C)，73.8(CH)，65.8(CH)，62.0(CH
2)，56.5(CH)，55.5(CH)，44.9(CH)，42.53(C)，42.47(CH)，41.0(C)，40.3(CH
2)，39.8(CH)，36.4(CH)，34.9(CH
2)，33.9(CH
2)，31.1(CH
2)，30.8(CH
2)，29.3(CH
2)，27.7(CH
2)，26.8(CH
2)，23.8(CH
2)，21.7(CH
3)，18.3(CH
3)，18.1(CH
3)，18.0(CH
3)，13.1(CH
3).
Purpose product 2:24-methylene radical-courage steroid-3 β, 5 α, 6 β, the structural identification of 19-tetrol
Fusing point: 223-225 ℃
Ultimate analysis: C
28H
48O
4Measured value: C, 75.20; H, 10.36 theoretical values: C, 74.95; H, 10.78,
MS：[M-H
2O]
+＝432，
IR：3416，3028，2936，2868，1642，1464，1377，1057
1HNMR(DMSO)：
5.25(1H，d，6β-OH)，4.71(1H，d，J＝1.5Hz，28-CH)，4.65(1H，d，J＝1.5Hz，28-CH)，4.51(1H，d，19-OH)，4.16(1H，d，3-CH)，4.01(1H，d，19-CH)，3.84(1H，m，3-CH)，3.64(1H，s，5-OH)，3.23(1H，m，6-CH)，2.25(1H，m，25-CH)，1.13(6H，d，26-CH
3，27-CH
3)，1.01(3H，s，19-CH
3)，0.87(3H，d，21-CH
3)，0.67(3H，s，18-CH
3).
13CNMR(DMSO)：
156.6(C)，107.3(CH
2)，75.4(C)，74.7(CH)，66.7(CH)，63.0(CH
2)，57.4(CH)，56.7(CH)，45.9(CH)，43.5(C)，43.3(CH)，42.8(C)，41.3(CH
2)，40.9(CH)，37.4(CH
2)，36.1(CH)，33.9(CH
2)，31.8(CH
2)，31.4(CH
2)，30.5(CH
2)，28.7(CH
2)，27.9(CH
2)，24.70(CH
2)，22.64(CH
3)，22.57(CH
3)，19.4(CH
3)，13.1(CH
3).
Purpose product 3: courage steroid-3 β, 5 α, 6 β, the structural identification of the two hydrazones of 19-tetrahydroxy-24-
Fusing point: 270-272 ℃
Ultimate analysis: C
54H
92O
4N
2Measured value: C, 70.92; H, 10.44; N, 2.98 theoretical values: C, 72.27; H, 10.33; N, 3.12
MS：[M+1]
+＝897
IR：3318，2943，2870，1628，1464，1379，1344，1060，976。
1HNMR(DMSO)：
5.38(1H，t，6β-H)，4.71(1H，d，J＝1.5Hz，28-CH)，4.65(1H，d，J＝1.5Hz，28-CH)，3.52(1H，m，3-CH)，2.28(1H，m，25-CH)，1.13(6H，d，26-CH
3，27-CH
3)，1.01(3H，s，19-CH
3)，0.91(3H，d，21-CH
3)，0.69(3H，s，18-CH
3).
13CNMR(DMSO)：
169.3(C)，75.4(C)，74.7(CH)，66.8(CH)，63.6(CH
2)，57.5(CH)，56.4(CH)，45.9(CH)，43.5(C)，42.8(C)，41.3(CH
2)，40.8(CH)，37.4(CH
2)，35.8(CH)，35.6(CH
2)，33.9(CH
2)，31.8(CH
2)，31.4(CH
2)，30.5(CH
2)，28.7(CH
2)，27.9(CH
2)，24.70(CH
2)，22.5(CH
3)，21.4(CH
3)，19.2(CH
3)，18.9(CH
3)，13.1(CH
3).
Claims (8)
1. courage steroid-3 β, 5 α, 6 β, the synthetic method of 19-tetrahydroxy-24-ketone and derivative, it is characterized in that with the Hyodeoxycholic Acid being raw material, prepare 3 β-acetoxyl group-courage steroid-5-alkene-24-acid, by become courage steroid acyl chlorides with the sulfur oxychloride prepared in reaction, the ultrasonic wave radiation down and the sec.-propyl cadion react 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone, obtain 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone with N-bromo-succinimide/high chloro acid solution's system reaction again, generate 3 β-acetoxyl group-courage steroid-5 α-bromo-6 β with the diacetoxy phenyl-iodide afterwards, 19-epoxy-24-ketone, generate 3 β with zinc powder/Glacial acetic acid reduction system, 19-diacetoxy-courage steroid-5-alkene-24-ketone; Use 5,6 two keys of oxygenant oxidation again, hydrolysis reaction gets courage steroid-3 β, 5 α, 6 β, 19-tetrahydroxy-24-ketone; Last and methyltriphenylphosphonium bromide reacts Synthetic 2 4-methylene radical-courage steroid-3 β, 5 α, 6 β, 19-tetrol; With synthetic courage steroid-3 β of hydrazine reaction, 5 α, 6 β, the two hydrazones of 19-tetrahydroxy-24-.
2. synthetic method according to claim 1 is characterized in that concrete reactions steps is:
(1) IV is dissolved in dry-out benzene and adds sulfur oxychloride, add the pyridine of catalytic amount, at room temperature stirred 2～4 hours, be evaporated to driedly, add benzene again and continue to concentrate, take residual sulfur oxychloride out of, yellow heavy-gravity liquid;
(2) take by weighing dry magnesium powder, add anhydrous diethyl ether, drip different N-PROPYLE BROMIDE/anhydrous ether solution, add back ultrasonic radiation 15～30 minutes, add Cadmium chloride fine powder after the cooling in batches, stirring under the ultrasonic wave radiation under 25～40 ℃, the ice bath cooling down, slowly be added drop-wise to 30～40% dry-out benzene solution of product of last step in the reaction system, drip off the back and continue ultrasonic wave radiation backflow 1～2 hour, after the ice bath cooling, drip 1: 1 aqueous hydrochloric acid, extract with benzene, the benzene layer is washed till neutrality with distilled water, drying, concentrating under reduced pressure, silica gel column chromatography gets white solid V;
(3) extracting waste solid V adds organic solvent dissolution, adds HClO again
4And water, under the lucifuge condition, adding the N-succimide then in batches, controlled temperature is lower than 10 ℃, reacts 1～2 hour down at 15～20 ℃ afterwards, adds 10%Na in reaction solution
2S
2O
8The aqueous solution, after the layering, the upper strata concentrates, the CH of lower floor
2Cl
2Extraction merges organic layer, uses saturated NaHCO
3Solution washing is washed with distilled water to neutrality again, drying, and concentrating under reduced pressure, silica gel column chromatography gets white solid VI;
(4) get compound VI, dissolve in hexanaphthene/benzene mixed solution, add oxygenant, under 20～40 ℃ of stirrings, ultra violet lamp 7～8 hours, reaction solution is used 10% sodium thiosulfate solution successively, saturated NaHCO
3Solution and distilled water wash are extremely neutral, drying, and concentrating under reduced pressure gets light yellow compound VI I;
(5) get compound VIII and add the Glacial acetic acid dissolving, add zinc powder, stirring and refluxing 20～24 hours; Suction filtration while hot, filtrate is used dichloromethane extraction, extraction liquid is washed till neutrality with saturated sodium bicarbonate solution and distilled water respectively, drying, concentrating under reduced pressure, silica gel column chromatography, light yellow thick liquid VIII;
(6) get compound VIII and add the methylene dichloride dissolving, add oxygenant, stir under the room temperature, methylene dichloride is removed in decompression, the clinker acetic acid ethyl dissolution adds the washing of 10% sodium sulfite solution then to colourless, is washed to neutrality, drying, concentrating under reduced pressure gets white solid IXa, it is added acetone solution, add perchloric acid, stir under the room temperature, transfer pH to neutral, pressure reducing and steaming acetone is used dichloromethane extraction, drying, concentrating under reduced pressure gets white solid X;
(7) get compound VIII and add the dissolving of 88% formic acid, boiling water bath heating 5 minutes is cooled to room temperature, adds oxygenant, room temperature was placed 24 hours, behind the dilute with water, use ethyl acetate extraction, add the washing of 10% sodium sulfite solution then to colourless, be washed to neutrality, drying, concentrating under reduced pressure gets white solid IXb;
(8) will go up step product IXb or X is dissolved in the methyl alcohol, adding concentration is 3% potassium hydroxide alcoholic solution, reflux 15～30 minutes, it is neutral transferring pH, methyl alcohol is removed in underpressure distillation, ethyl acetate extraction, the organic layer drying, the pressure reducing and steaming solvent gets light yellow solid, silica gel column chromatography gets white solid I;
(9) methyltriphenylphosphonium bromide is added in the anhydrous tetrahydrofuran solution, inject n-Butyl Lithium, injection rate just is dissolved as suitable with methyltriphenylphosphonium bromide, stirring reaction is 4～6 hours under the room temperature, I in the last step is added reaction system, continue reaction 2～3 hours, reaction solution is poured into rapidly in the saturated ammonium chloride solution, use extracted with diethyl ether, ether layer drying, the pressure reducing and steaming solvent gets light yellow solid, silica gel column chromatography gets white solid II;
(10) I is added dissolve with ethanol, add in the aqueous solution of hydrazine, separate thermal backflow, the pressure reducing and steaming solvent adds entry, and it is neutral transferring pH, and ethyl acetate extraction gets white solid, and silica gel column chromatography gets white solid III;
In the above-mentioned steps, I represents courage steroid-3 β, 5 α, 6 β, 19-tetrahydroxy-24-ketone; II represents 24-methylene radical-courage steroid-3 β, 5 α, 6 β, 19-tetrol; III represents courage steroid-3 β, 5 α, 6 β, the two hydrazones of 19-tetrahydroxy-24-; IV represents 3 β-acetoxyl group-courage steroid-5-alkene-24-acid; V represents 3 β-acetoxyl group-courage steroid-5-alkene-24-ketone; VI represents 3 β-acetoxyl group-courage steroid-5 α-bromo-6 beta-hydroxies-24-ketone; VII represents 3 β-acetoxyl group-courage steroid-5 α-bromo-6 β, 19-epoxy-24-ketone; VIII represents 3 β, 19-diacetoxy-courage steroid-5-alkene-24-ketone; IXa represents 3 β, 19-diacetoxy-courage steroid-5,6 beta epoxides-24-ketone; IXb represents 3 β, 19-diacetoxy-courage steroid-5,6 α-epoxy-24-ketone; X represents 3 β, 19-diacetoxy-courage steroid-5,6-dihydroxyl-24-ketone.
3. synthetic method according to claim 2 is characterized in that the concentration of the benzole soln of II in the step (1) is 25～45%, and the amount of sulfur oxychloride is 1.0～2.0 times of mole number of II.
4. synthetic method according to claim 2, the amount of magnesium powder in the step (2) of it is characterized in that are 1.2～3.0 times of mole number of II.
5. synthetic method according to claim 2 is characterized in that the organic solvent in the step (3) is tetrahydrofuran (THF) or dioxane.
6. synthetic method according to claim 2 is characterized in that the oxygenant in the step (4) is diacetoxy phenyl-iodide or lead tetra-acetate.
7. synthetic method according to claim 2 is characterized in that the oxygenant in the step (6) is potassium permanganate/copper sulfate or metachloroperbenzoic acid.
8. synthetic method according to claim 2 is characterized in that the oxygenant in the step (7) is 30% hydrogen peroxide.
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| CNB200510121374XA CN100436474C (en) | 2005-12-31 | 2005-12-31 | Process for synthesizing cholester-3 bata, 5 alpha, 6 bata, 19-tetrahydroxy-24-one and derivative |
| PCT/CN2006/001627 WO2007076655A1 (en) | 2005-12-31 | 2006-07-10 | METHOD FOR SYNTHESIS OF CHOLEST-3β,5α,6β,19-TETRAHYDROXY-24-ONE AND ITS DERIVATIVES |
| AU2006332419A AU2006332419A1 (en) | 2005-12-31 | 2006-07-10 | The use of phthalide derivatives |
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| 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 |
| WO2016165496A1 (en) * | 2015-04-14 | 2016-10-20 | 诺瑞特国际药业股份有限公司 | Method for preparing deoxycholic acid |
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| CN114671796A (en) * | 2022-04-22 | 2022-06-28 | 宁波工程学院 | Method for synthesizing N-alkyl phthalimide through photocatalysis |
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| JPS5573700A (en) * | 1978-11-30 | 1980-06-03 | Teijin Ltd | Preparation of steroidal ketone compound |
| CA2157594A1 (en) * | 1993-03-10 | 1994-09-15 | Leah L. Frye | Steroid derivatives, pharmaceutical compositions containing them, and their use as antibiotics or disinfectants |
| CN1448399A (en) * | 2003-04-24 | 2003-10-15 | 中山大学 | Synthetic method of 24-methylene-cholesterol-5-alkenyl-3 beta, 19-glycol |
| CN1448400A (en) * | 2003-05-06 | 2003-10-15 | 中山大学 | Synthetic method of 24-methylene-cholesterol-3 beta, 5 alpha, 6 beta,19-tetraalcohol |
| CN1583781A (en) * | 2004-05-28 | 2005-02-23 | 中山大学 | Synthesis of 3 beta, 7 beta, 19-tricarboxy-5-ene-cholestane |
| CN1583782A (en) * | 2004-05-28 | 2005-02-23 | 中山大学 | Synthesis of 24-submethyl-cholesterol-5-ene-3 beta, 7 beta, 19-trialcohol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| WO2016165496A1 (en) * | 2015-04-14 | 2016-10-20 | 诺瑞特国际药业股份有限公司 | Method for preparing deoxycholic acid |
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