CN101220073B - Synthesis of polyhydroxy ocean steroid (25R)-5 alpha-cholesteric-2 beta,3 alpha,26-triol - Google Patents
Synthesis of polyhydroxy ocean steroid (25R)-5 alpha-cholesteric-2 beta,3 alpha,26-triol Download PDFInfo
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Abstract
The invention discloses a synthetic method of a polyhydroxy marine steroid (25R)-5 Alpha- cholest-2 Beta and a 3 Alpha and 26-triol, which uses a low-cost Tigogenin as the raw material and obtains (25R)-5 Alpha-cholest-2-ene-16 Beta and 26-diol through the TsCl esterification, elimination reaction and the reduction of zinc powder/ethanol system, obtains (25R)-26-O- t butyl dimethysilyl-5 Alpha- cholest-2-ene through selectively protecting C-26- hydroxyl, C-16-hydroxyl ethlsulphonic acid esterification and lithium aluminum hydride reduction by t-butyl dimethylsilyl chloride, and at last gets the object compound (25R)-5 Alpha- cholest-2 Beta, 3 Alpha and 26-triol through ring-opening under the acid conditions after the epoxidation. The synthetic route of the invention is characterized in that: the synthetic raw material is of low-cost and easy to get; the synthetic route is scientific and reasonable, etc. The target compound has potential antitumor and antivirus activity.
Description
Technical field
The present invention relates to a kind of synthetic method of polyhydroxy ocean steroidal.
Background technology
Marine organisms have been developed its unique metabolic way under its special environment, a large amount of structures are peculiar, physiologically active is extremely strong and act on special material thereby containing.The ocean sterol is biomembranous important component part, also is the precursor of some hormone, has very strong biological activity, (25R)-5 α-courage steroid-2 β, 3 α, 26-triol be a kind of polyhydroxy ocean steroidal compound of from marine organisms (Ophiarachna incrassara), finding (M.ValeriaD ' Auria, J.Org.Chem, 1987,52 (18), 3947-3952), its structural formula as I, the prosposition of Compound I has 2 β respectively, 3 α hydroxyls have unique 26-hydroxyl on 17 side chains.
This compound and derivative thereof be expected to as antitumor, antiviral, reducing blood-fat; (XIONG Fu, Journal of Natnral Products, 1994 are further studied in aspects such as neuroprotective; 57; (11), 1591-1594); but the content of this compound in marine organisms is very low; still the synthetic method of not having at present this compound of bibliographical information, for further studying the pharmacologically active of this compound and derivative, the applicant has carried out the study on the synthesis of this compound.
Summary of the invention
The purpose of this invention is to provide a kind of polyhydroxy ocean steroidal (25R)-5 α-courage steroid-2 β, 3 α, the synthetic method of 26-triol, this method have characteristics such as raw material is cheap and easy to get, reaction conditions is gentle, selectivity is good, productive rate height.
Synthetic method of the present invention is to be raw material with the Tigogenin, by Tosyl chloride esterification, elimination reaction and zinc powder/ethanol system reduce (25R)-5 α-courage steroid-2-alkene-16 β, the 26-glycol; Through TERT-BUTYL DIMETHYL CHLORO SILANE selective protection C-26-hydroxyl, the sulfonic acid esterification of C-16-hydroxymethyl and Lithium Aluminium Hydride reduce (25R)-26-O-tertiary butyl dimethyl silica-based-5 α-courage steroid-2-alkene; By epoxidation, the acidic conditions open loop gets target compound (25R)-5 α-courage steroid-2 β, 3 α, 26-triol at last.Reaction formula of the present invention can be represented with following synthetic route:
I:R
1=R
2=R
3=OH, (25R)-5 α-courage steroid-2 β, 3 α, 26-triol; II:R
1=H, R
2=OH Tigogenin; III:R
1=H, R
2=OTs Tigogenin p-toluenesulfonic esters; IV:R
1=R
2=H, (25R)-5 α-spiral shell steroid-2-alkene; V:R
1=R
2=H, R
3=R
4=OH, (25R)-5 α-courage steroid-2-alkene-16 β, the 26-glycol; VI:R
1=R
2=H, R
3=OTBDMS, R
4=OH, (25R)-26-O-tertiary butyl dimethyl is silica-based-5 α-courage steroid-2-alkene-16 β-alcohol; VII:R
1=R
2=H, R
3=OTBDMS, R
4=OMs, (25R)-26-O-tertiary butyl dimethyl is silica-based-5 α-courage steroid-2-alkene-16 Beta-methyl sulphonate; VIII:R
1=R
2=H, R
3=OTBDMS, R
4=H, (25R)-26-O-tertiary butyl dimethyl is silica-based-5 α-courage steroid-2-alkene; IX:R
1=R
2=O, R
3=OTBDMS, (25R)-silica-based-2 α of 26-O-tertiary butyl dimethyl, 3 α-epoxy-courage steroid.
Concrete reactions steps of the present invention is:
(1) Tigogenin II is dissolved in the dry pyridine, adds Tosyl chloride, reaction solution is slowly poured among 17% (w/w) HCl, suction filtration, and precipitation washes with water to neutrality, the dry white solid compound Tigogenin p-toluenesulfonic esters III that gets;
(2) compound III is dissolved among the dry DMF, adds LiBr and Li
2CO
3, after reaction finished, reaction solution was cooled to room temperature, slowly pour among 10% (w/w) HCl, and suction filtration, precipitation washes with water to neutrality, the dry pressed powder compound IV that gets;
(3) compound IV is dissolved in the ethanol, add zinc amalgam, refluxing drips concentrated hydrochloric acid down, and TLC follows the tracks of reaction, stopped reaction after raw material disappears, remove by filter inorganic precipitation, most of ethanol is removed in decompression, uses dichloromethane extraction 1～3 time, organic layer washes with water to neutrality, anhydrous sodium sulfate drying, concentrate white solid, silicon
Plastic column chromatography purify white solid compound V;
(4) compound V is dissolved in the anhydrous solvent, adds imidazoles and TERT-BUTYL DIMETHYL CHLORO SILANE, stirring reaction spends the night under the room temperature, after reaction finished, reaction solution was poured in the water and is disperseed, dichloromethane extraction 1～3 time, organic layer washes with water, anhydrous sodium sulfate drying, concentrate the yellow oil compound VI;
(5) compound VI is dissolved in the anhydrous pyridine, add Methanesulfonyl chloride under the ice-water bath condition, temperature rose to after the room temperature stirring reaction 4～8 hours, TCL detects raw material and disappears, and adds the shrend reaction of going out, dichloromethane extraction, organic phase is with 5% (w/w) dilute hydrochloric acid flush away pyridine, be washed to neutrality, anhydrous sodium sulfate drying, concentrate yellow oil compound VI I;
(6) compound VI I is dissolved in the anhydrous solvent, slowly add lithium aluminum hydride in batches, stirring reaction under the room temperature, TCL detect raw material and disappear, and add quencher and finish reaction, filter, organic layer washes to neutrality anhydrous sodium sulfate drying with water again with the washing of 5% (w/w) dilute hydrochloric acid, concentrate reddish-brown oily matter, silica gel column chromatography purify oily compound VIII;
(7) compound VIII is dissolved in the methylene dichloride, when using first kind of oxidation system, adds entry, yellow soda ash and metachloroperbenzoic acid successively, reaction 4～8h; When using second kind of oxidation system, add potassium permanganate/copper sulphate powder, the trimethyl carbinol and water successively, 2～6h; Reaction finishes the back concentrating under reduced pressure and removes methylene dichloride, residue water ethyl acetate extraction, and organic layer is used respectively that 5% (w/w) S-WAT is washed, saturated sodium bicarbonate is washed, is washed respectively 1～3 time, and anhydrous sodium sulfate drying, concentrating under reduced pressure get faint yellow oily thing IX;
(8) Compound I X is dissolved in the acetone, adds acid hydrolysis, reaction knot speed back pressure reducing and steaming acetone adds ethyl acetate extraction, and organic layer is used saturated sodium sulfite, saturated sodium bicarbonate successively, saturated aqueous common salt and water washing.Anhydrous sodium sulfate drying, crude product through silica gel column chromatography purify white solid I.
In the above-mentioned reactions steps, the mol ratio of II and Tosyl chloride is 1: 1～2 in the step (1), and the reaction times is 20～30h; III, LiBr and Li in the step (2)
2CO
3Mol ratio be 1: 10～15: 10～15, the reaction times is 1～4h, temperature of reaction is 110～155 ℃; The mol ratio of IV and zinc amalgam is 1: 140～240 in the step (3); Solvent is DMF, THF or methylene dichloride in the step (4), and the mol ratio of V, imidazoles and TERT-BUTYL DIMETHYL CHLORO SILANE is 1: 1～3: 1～3; The mol ratio of VI and Methanesulfonyl chloride is 1: 1～3 in the step (5); In the step (6), the mol ratio of VII and lithium aluminum hydride is 1: 1～3, and the reaction times is 24～48h, and anhydrous solvent is ether or tetrahydrofuran (THF), and quencher is sodium sulfate crystal (Na
2SO
4.10H
2O) or water (H
2O); In the step (7), be 1g: 40～60mL: 30～40mL to the amount ratio of first kind of oxidation system: VIII, methylene dichloride and water, the mol ratio of VIII, yellow soda ash and metachloroperbenzoic acid is 1: 2.5～4: 1.5～3; Amount ratio to second kind of oxidation system: VIII, methylene dichloride, the trimethyl carbinol and water is: 1g: 10～20mL: 1～3mL: 0.2～0.6mL, and the mol ratio of VIII, potassium permanganate and copper sulfate is: 1: 10～15: 5～8; Acid is perchloric acid or sulfuric acid in the step (8), and the mol ratio of IX and perchloric acid is 1: 3～6, and IX and vitriolic mol ratio are 1: 2～4, and the reaction times is 12～24h.
Embodiment
The synthetic route of the present invention's design has characteristics such as synthesis material is cheap and easy to get, and synthetic route is scientific and reasonable, and target compound has antitumor, the antiviral activity of potential.
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:R
1=R
2=R
3=OH, (25R)-5 α-courage steroid-2 β, 3 α, 26-triol; II:R
1=H, R
2=OH Tigogenin; III:R
1=H, R
2=OTs Tigogenin p-toluenesulfonic esters; IV:R
1=R
2=H, (25R)-5 α-spiral shell steroid-2-alkene; V:R
1=R
2=H, R
3=R
4=OH, (25R)-5 α-courage steroid-2-alkene-16 β, the 26-glycol; VI:R
1=R
2=H, R
3=OTBDMS, R
4=OH, (25R)-26-O-tertiary butyl dimethyl is silica-based-5 α-courage steroid-2-alkene-16 β-alcohol; VII:R
1=R
2=H, R
3=OTBDMS, R
4=OMs, (25R)-26-O-tertiary butyl dimethyl is silica-based-5 α-courage steroid-2-alkene-16 Beta-methyl sulphonate; VIII:R
1=R
2=H, R
3=OTBDMS, R
4=H, (25R)-26-O-tertiary butyl dimethyl is silica-based-5 α-courage steroid-2-alkene; IX:R
1=R
2=O, R
3=OTBDMS, (25R)-silica-based-2 α of 26-O-tertiary butyl dimethyl, 3 α-epoxy-courage steroid.
Embodiment 1
(25R)-5 α that embodiment 1 provides-courage steroid-2 β, 3 α, the synthetic method of 26-triol comprises the steps:
(1). Tigogenin II 50g (0.12mol) is dissolved in the 250ml dry pyridine, adds Tosyl chloride 45.8g (0.24mol), stirring reaction 24h under the room temperature.Reaction solution is slowly poured among 1000ml17% (w/w) HCl, separates out white precipitate, suction filtration, and precipitation washes with water to neutrality, dry 68g white solid compound III, the productive rate 99% of getting.
(2). compound III 30g (0.053mol) is dissolved among the dry DMF of 450ml, adds LiBr 45.6g (0.53mol) and Li
2CO
339.2g (0.53mol), backflow 1.5h.Slowly pour among 10% (w/w) HCl after being cooled to room temperature, suction filtration, precipitation is washed to neutrality, the dry white solid powder compounds IV23g that gets.Productive rate 87.8%.
(3). one mechanical stirring is housed, constant pressure funnel adds compound IV (15g in three mouthfuls of round-bottomed flasks of the 2L of reflux condensing tube successively, 37.7mmol) and 1100ml ethanol, add zinc amalgam 585g, refluxing drips concentrated hydrochloric acid 400ml down, TLC follows the tracks of reaction, stopped reaction after raw material disappears.Filter, most of ethanol is removed in decompression, and with dichloromethane extraction 250ml * 3 times, organic layer washes with water to neutrality, anhydrous sodium sulfate drying, concentrate the 13g white solid.Silica gel column chromatography (ethyl acetate: sherwood oil, V: V=3: 7) purify white solid compound V 10.8g, productive rate 71.3%.
(4). compound V (30g 74.6mmol) is dissolved in the dry DMF (300ml), add imidazoles (15.2g, 3eq) and TERT-BUTYL DIMETHYL CHLORO SILANE (22.5g, 2eq), stirring reaction spends the night under the room temperature.TCL detects raw material and disappears, and pours in 3 times of water gagings and disperses DMF, and dichloromethane extraction 3 times wash 3 times, anhydrous sodium sulfate drying, concentrated yellow oil compound VI 57g.Productive rate 86.3%.
(5). compound VI (5g, 9.67mmol) being dissolved in the 30ml anhydrous pyridine, stirring and dissolving adds Methanesulfonyl chloride (2.25ml under the ice-water bath condition, 3eq), temperature rose to after the room temperature stirring reaction 4 hours, added the shrend reaction of going out, dichloromethane extraction, organic phase is with 5% (w/w) dilute hydrochloric acid flush away pyridine, be washed to neutrality, anhydrous sodium sulfate drying, concentrate yellow oil 5.2g.Silica gel column chromatography (ethyl acetate: sherwood oil, V: V=1: 10) purify faint yellow oily compound VI I4.6g, productive rate 80%.
(6). (17g 29.16mmol) is dissolved among the anhydrous diethyl ether 510ml compound VI I, and slowly add lithium aluminum hydride (2.2g, 2eq), stirring reaction 36h under the room temperature, TLC detect raw material and disappear in batches.Add the sodium sulfate cancellation reaction that contains crystal water, filter, filter residue washes twice with ethyl acetate, and organic layer merges, and with the washing of 5% (w/w) dilute hydrochloric acid, organic layer washes with water to neutrality again, anhydrous sodium sulfate drying, concentrated 14g reddish-brown oily matter.Silica gel column chromatography (ethyl acetate: sherwood oil, V: V=1: 15) purify oily compound VIII8.9g, productive rate 79%.
(7). with compound VIII (16g 0.032mol) is dissolved in the 750ml methylene dichloride, add entry 450ml and yellow soda ash (13.6g, 0.128mol).Slow adding metachloroperbenzoic acid under the stirring at room (13.7g, 0.0832mol).Finish reaction behind the 6h, concentrate and remove methylene dichloride, water ethyl acetate extraction, organic phase are used 5% (w/w) S-WAT, saturated sodium bicarbonate and washing respectively each three times, and anhydrous sodium sulfate drying, concentrating under reduced pressure get the faint yellow oily thing of 17g.Silica gel column chromatography (ethyl acetate: sherwood oil, V: V=1: 15) purify oily compound IX10.9g, productive rate 66%.
(8). Compound I X (4g 7.75mmol) is dissolved among the acetone 200ml, add entry 18.6ml and 70% perchloric acid (2.7ml, 4eq).The stirring at room reaction is spent the night, and reaction finishes the back decompression and removes acetone, adds ethyl acetate extraction, and organic phase is used saturated sodium sulfite, saturated sodium bicarbonate washing, saturated aqueous common salt and washing successively.Anhydrous sodium sulfate drying, concentrate white solid 6g.Silica gel column chromatography (acetone: sherwood oil, V: V=3: 7) purify white solid Compound I 3g.Productive rate 93%.
Embodiment 2
(25R)-5 α that embodiment 2 provides-courage steroid-2 β, 3 α, the synthetic method of 26-triol comprises the steps:
(1). with embodiment 1. (1).
(2). compound III 30g (0.053mol) is dissolved among the dry DMF of 450ml, adds LiBr 45.6g (0.53mol) and Li
2CO
339.2g (0.53mol), 110 ℃ of backflow 4h.Slowly pour among 10% (w/w) HCl after being cooled to room temperature, suction filtration, precipitation is washed to neutrality, dry white solid powder compounds IV23g, the productive rate 82% of getting.
(3)～(8). with embodiment 1 (3)～(8).
Embodiment 3
(25R)-5 α that embodiment 3 provides-courage steroid-2 β, 3 α, the synthetic method of 26-triol comprises the steps:
(1)～(2). with embodiment 1. (1)～(2).
(3). one mechanical stirring is housed, constant pressure funnel adds compound IV (15g in three mouthfuls of round-bottomed flasks of the 2L of reflux condensing tube successively, 37.7mmol) and 1100ml ethanol, add zinc amalgam 445g, refluxing drips concentrated hydrochloric acid 300ml down, TLC follows the tracks of reaction, stopped reaction after raw material disappears.Filter, most of ethanol is removed in decompression, and with dichloromethane extraction 250ml * 3 times, organic layer washes with water to neutrality, anhydrous sodium sulfate drying, concentrate the 13g white solid.Silica gel column chromatography (ethyl acetate: sherwood oil, V: V=3: 7) purify white solid compound V 10.8g, productive rate 65%.
(4)～(8). with embodiment 1. (4)～(8).
Embodiment 4
(25R)-5 α that embodiment 4 provides-courage steroid-2 β, 3 α, the synthetic method of 26-triol comprises the steps:
(1)～(6). with embodiment 1. (1)～(6).
(7). (4g 0.008mol) is dissolved in the 40mL methylene dichloride, adds cupric sulfate crystals and potassium permanganate mix powder 24g, adds an amount of trimethyl carbinol of 4mL and 0.8mL water again, stirs 2 hours under the room temperature with compound VIII.Methylene dichloride is removed in decompression, and water ethyl acetate extraction, organic phase are used 5% (w/w) S-WAT, saturated sodium bicarbonate and washing respectively each three times, and anhydrous sodium sulfate drying, concentrating under reduced pressure get the faint yellow oily thing of 3.6g, productive rate 87%.
(8) (2g 7.75mmol) is dissolved among the acetone 100ml Compound I X, adds an amount of 10mL2MH
2SO
4, stirred 24 hours under the room temperature, transfer pH to neutral with saturated sodium bicarbonate solution, acetone is removed in decompression, adds ethyl acetate extraction, and organic phase is used saturated sodium sulfite, saturated sodium bicarbonate washing, saturated aqueous common salt and washing, anhydrous sodium sulfate drying successively.Silica gel column chromatography (ethyl acetate: sherwood oil, V: V=3: 7) purify white solid Compound I 1.3g, productive rate 85%.
The spectral data of target compound:
1H?NMR(DMSO，400MHz)，δ(ppm)：0.613(s，3H，18-Me)，0.80(d，3H，27-Me，J＝6.4Hz)，0.88(d，3H，21-Me，J＝6.4Hz)，0.903(s，3H，19-Me)，3.15～3.17(m，1H，26-Ha)，3.21～3.23(m，1H，26-Hb)，3.55～3.60(m，2H，2α-H?and?3β-H).
13C?NMR(DMSO，400MHz)，δ(ppm)：12.40(CH
3)，14.42(CH
3)，17.18(CH
3)，18.95(CH
3)，20.89(CH
2)，23.34(CH
2)，24.26(CH
2)，28.26(CH
2)，28.52(CH
2)，31.85(CH
2)，32.31(CH
2)，33.73(CH
2)，34.94(CH)，35.61(CH)，35.80(CH)，35.80(C)，36.19(CH
2)，38.85(CH)，39.96(CH
2)，40.11(CH
2)，42.66(C)，55.25(CH)，56.20(CH)，56.55(CH)，66.84(CH
2)，69.56(CH)，70.51(CH).
IR(KBr)v(cm
-1)：3352，2927，1446，1382，1036.
Anal.calcd?for?C
27H
48O
3：C?77.09，H?11.50，found?C?77.16，H?11.58.
Claims (10)
1. polyhydroxy ocean steroidal (25R)-5 α-courage steroid-2 β, 3 α, the synthetic method of 26-triol is characterized in that with the Tigogenin being raw material, by Tosyl chloride esterification, elimination reaction and zinc powder/ethanol system reduce (25R)-5 α-courage steroid-2-alkene-16 β, the 26-glycol; Through TERT-BUTYL DIMETHYL CHLORO SILANE selective protection C-26-hydroxyl, the sulfonic acid esterification of C-16-hydroxymethyl and Lithium Aluminium Hydride reduce (25R)-26-O-tertiary butyl dimethyl silica-based-5 α-courage steroid-2-alkene; By epoxidation, the acidic conditions open loop gets target compound (25R)-5 α-courage steroid-2 β, 3 α, 26-triol at last.
2. synthetic method according to claim 1 is characterized in that concrete reactions steps is:
(1) Tigogenin II is dissolved in the dry pyridine, adds Tosyl chloride, reaction solution is slowly poured among 17% (w/w) HCl, suction filtration, and precipitation washes with water to neutrality, the dry white solid compound Tigogenin p-toluenesulfonic esters III that gets;
(2) compound III is dissolved among the dry DMF, adds LiBr and Li
2CO
3, after reaction finished, reaction solution was cooled to room temperature, slowly pour among 10% (w/w) HCl, and suction filtration, precipitation washes with water to neutrality, the dry pressed powder compound IV that gets;
(3) compound IV is dissolved in the ethanol, add zinc amalgam, refluxing drips concentrated hydrochloric acid down, and TLC follows the tracks of reaction, stopped reaction after raw material disappears, remove by filter inorganic precipitation, most of ethanol is removed in decompression, uses dichloromethane extraction 1～3 time, organic layer washes with water to neutrality, anhydrous sodium sulfate drying, concentrate white solid, silica gel column chromatography purify white solid compound V;
(4) compound V is dissolved in the anhydrous solvent, adds imidazoles and TERT-BUTYL DIMETHYL CHLORO SILANE, stirring reaction spends the night under the room temperature, after reaction finished, reaction solution was poured in the water and is disperseed, dichloromethane extraction 1～3 time, organic layer washes with water, anhydrous sodium sulfate drying, concentrate the yellow oil compound VI;
(5) compound VI is dissolved in the anhydrous pyridine, add Methanesulfonyl chloride under the ice-water bath condition, temperature rose to after the room temperature stirring reaction 4～8 hours, TCL detects raw material and disappears, and adds the shrend reaction of going out, dichloromethane extraction, organic phase is with 5% (w/w) dilute hydrochloric acid flush away pyridine, be washed to neutrality, anhydrous sodium sulfate drying, concentrate yellow oil compound VI I;
(6) compound VI I is dissolved in the anhydrous solvent, slowly add lithium aluminum hydride in batches, stirring reaction under the room temperature, TCL detect raw material and disappear, and add quencher and finish reaction, filter, organic layer washes to neutrality anhydrous sodium sulfate drying with water again with the washing of 5% (w/w) dilute hydrochloric acid, concentrate reddish-brown oily matter, silica gel column chromatography purify oily compound VIII;
(7) compound VIII is dissolved in the methylene dichloride, when using first kind of oxidation system: add entry, yellow soda ash and metachloroperbenzoic acid successively, reaction 4～8h, when using second kind of oxidation system: add potassium permanganate/copper sulphate powder, the trimethyl carbinol and water successively, reaction 2-6h, reaction finishes the back concentrating under reduced pressure and removes methylene dichloride, residue water ethyl acetate extraction, organic layer is used respectively that 5% (w/w) S-WAT is washed, saturated sodium bicarbonate is washed, is washed each 1～3 time, anhydrous sodium sulfate drying, concentrating under reduced pressure get faint yellow oily thing IX;
(8) Compound I X is dissolved in the acetone, adds acid hydrolysis, reaction finishes back pressure reducing and steaming acetone, adds ethyl acetate extraction, and organic layer is used saturated sodium sulfite, saturated sodium bicarbonate successively, saturated aqueous common salt and water washing.Anhydrous sodium sulfate drying, crude product through silica gel column chromatography purify white solid I;
In the above-mentioned steps, I:(25R)-5 α-courage steroid-2 β, 3 α, 26-triol; II: Tigogenin; III: Tigogenin p-toluenesulfonic esters; IV:(25R)-5 α-spiral shell steroid-2-alkene; V:(25R)-and 5 α-courage steroid-2-alkene-16 β, the 26-glycol; VI:(25R)-and 26-O-tertiary butyl dimethyl is silica-based-5 α-courage steroid-2-alkene-16 β-alcohol; VII:(25R)-and 26-O-tertiary butyl dimethyl is silica-based-5 α-courage steroid-2-alkene-16 Beta-methyl sulphonate; VIII:(25R)-and 26-O-tertiary butyl dimethyl is silica-based-5 α-courage steroid-2-alkene; IX:(25R)-and silica-based-2 α of 26-O-tertiary butyl dimethyl, 3 α-epoxy-courage steroid.
3. synthetic method according to claim 2 is characterized in that in the step (1), the mol ratio of II and Tosyl chloride is 1: 1～2, and the reaction times is 20～30h.
4. synthetic method according to claim 2 is characterized in that in the step (2) III, LiBr and Li
2CO
3Mol ratio be 1: 10～15: 10～15, the reaction times is 1～4h, temperature of reaction is 110～155 ℃.
5. synthetic method according to claim 2 is characterized in that in the step (3), the mol ratio of IV and zinc amalgam is 1: 140～240.
6. synthetic method according to claim 2 is characterized in that in the step (4), solvent is DMF, THF or methylene dichloride, and the mol ratio of V, imidazoles and TERT-BUTYL DIMETHYL CHLORO SILANE is 1: 1～3: 1～3.
7. synthetic method according to claim 2 is characterized in that in the step (5), the mol ratio of VI and Methanesulfonyl chloride is 1: 1～3.
8. synthetic method according to claim 2 is characterized in that in the step (6), the mol ratio of VII and lithium aluminum hydride is 1: 1～3, and the reaction times is 24～48h, and anhydrous solvent is ether or tetrahydrofuran (THF), and quencher is sodium sulfate crystal or water.
9. synthetic method according to claim 2, it is characterized in that in the step (7), amount ratio to first kind of oxidation system: VIII, methylene dichloride and water is 1g: 40～60mL: 30～40mL, and the mol ratio of VIII, yellow soda ash and metachloroperbenzoic acid is 1: 2.5～4: 1.5～3; Amount ratio to second kind of oxidation system: VIII, methylene dichloride, the trimethyl carbinol and water is: 1g: 10～20mL: 1～3mL: 0.2～0.6mL, the mol ratio of VIII, potassium permanganate and copper sulfate is: 1: 10～15: 5～8.
10. synthetic method according to claim 2 is characterized in that in the step (8) that acid is perchloric acid or sulfuric acid, and the mol ratio of IX and perchloric acid is 1: 3～6, and IX and vitriolic mol ratio are 1: 2～4, and the reaction times is 12～24h.
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| CN103409144B (en) * | 2013-08-16 | 2014-11-26 | 东北大学 | Steroid-element-containing cyclic carbonate active liquid crystal monomer and preparation method thereof |
| CN115260271A (en) * | 2022-08-31 | 2022-11-01 | 沈阳化工研究院有限公司 | Method for removing 16, 26-sulfonate group from steroid compound |
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| GB727010A (en) * | 1950-12-27 | 1955-03-23 | Syntex Sa | Improvements in or relating to the manufacture of cyclopentano-polyhydrophenanthrenecompounds |
| CN1821260A (en) * | 2006-03-24 | 2006-08-23 | 中国科学院上海有机化学研究所 | Cholest compound, synthetic method and its use |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB727010A (en) * | 1950-12-27 | 1955-03-23 | Syntex Sa | Improvements in or relating to the manufacture of cyclopentano-polyhydrophenanthrenecompounds |
| CN1821260A (en) * | 2006-03-24 | 2006-08-23 | 中国科学院上海有机化学研究所 | Cholest compound, synthetic method and its use |
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| 金志敏等.多羟基甾醇25(R)-异螺甾环-5-烯-2β,3α,19-三醇的合成.有机化学27 9.2007,27(9),1142～1146. |
| 金志敏等.多羟基甾醇25(R)-异螺甾环-5-烯-2β,3α,19-三醇的合成.有机化学27 9.2007,27(9),1142～1146. * |
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