CN102180928B - 3-beta,5-alpha,6-beta-trihydroxy steroid compounds, and synthesis method and application thereof - Google Patents
3-beta,5-alpha,6-beta-trihydroxy steroid compounds, and synthesis method and application thereof Download PDFInfo
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Abstract
The invention discloses 3-beta,5-alpha,6-beta-trihydroxy steroid compounds, and a synthesis method and application thereof. In the invention, dehydrogenated epiandrosterone and progestin, which are used as raw materials, are epoxidated, and subjected to ring opening, Wittig reaction and reduction hydrogenation reaction to obtain the target compounds. Three of the target compounds have an obvious protective action on in-vitro glutamic acid induced neurons, and has dose-effect relationship.
Description
Technical field
The present invention relates to 3 β, 5 α, 6 β-trihydroxy steroid compounds and synthetic method thereof and application.
Background technology
Neuroactive steroid has substantial connection to neuronal damage, death and multiple central nervous system disease, at present with some steroid hormones as an alternative therapy apply to clinical.Oestrogenic hormon is the stronger neuroactive steroid of known neuroprotective, clinically oestrogenic hormon is used for the treatment of AD, receives good effect; Allopregnenolone can be protected the irreversible neurotoxic injury of cultured hippocampus cell that is caused by hypoxemia and L-glutamic acid.Dehydroepiandrosterone can reduce the neurotoxic effect of L-glutamic acid analogue and corticosteroid; The 7-hydroxyl goes epiandrosterone also to show obvious neuroprotective.Some studies show that: have 3 β, and 5 α, the compound of 6 β-trihydroxy-cyclopentanoperhydro-phenanthrene structure has significant neuroprotective, such as pregnant steroid-3 β of chemosynthesis, 5 α, the Neuron Apoptosis cell that 6 beta-triols are induced low potassium has significant provide protection.
Summary of the invention
The object of the present invention is to provide a kind of 3 β, 5 α, 6 β-trihydroxy-steroid compound.
The present invention also aims to provide 3 β, 5 α, the synthetic method of 6 β-trihydroxy-steroid compound, this synthetic method raw material is cheap and easy to get, and reaction conditions is gentle, and simple to operate, synthetic route is short.
Another object of the present invention is to provide 3 β, 5 α, 6 β-trihydroxy-steroid compound has application in the medicine of provide protection in preparation to the neuronal cell of glutamate induction.
3 β provided by the invention, 5 α, 6 β-trihydroxy-steroid compound have following structure:
Ⅰ-XⅢ
Described chemical compounds I-X III is respectively,
I: R
1=OTBDMS, R
2=R
3=H, R
4=OMe, 3-O-t-Butyldimethylsilyl-17-methoxyl group dehydroepiandros-sterone;
II: R
1=OH, R
2=R
3=O, R
4=OMe, 5 α, 6 alpha-epoxy-17s-methoxyl group-dehydroepiandros-sterone;
III: R
1=R
2=R
3=OH, R
4=OMe, 17-methoxyl group-androstane-3 β, 5 α, 6 beta-triols;
IV: R
1=R
2=R
3=OH, R
4=CH
2, 17-methylene radical-androstane-3 β, 5 α, 6 beta-triols;
V: R
1=R
2=R
3=OH, R
4=CHCH
3, 17-ethylidene-androstane-3 β, 5 α, 6 beta-triols;
VI: R
1=R
2=R
3=OH, R
4=CH CH
2CH
3, 17-propylidene-androstane-3 β, 5 α, 6 beta-triols;
VII: R
1=R
2=R
3=OH, R
4=iPr, 17-pseudoallyl-androstane-3 β, 5 α, 6 beta-triols;
VIII: R
1=R
2=R
3=OH, R
4=CH (CH
2)
2CH
3, 17-butylidene-androstane-3 β, 5 α, 6 beta-triols;
IX: R
1=R
2=R
3=OH, R
4=Me, 17-methyl-androstane-3 β, 5 α, 6 beta-triols;
X: R
1=R
2=R
3=OH, R
4=Et, 17-ethyl-androstane-3 β, 5 α, 6 beta-triols;
XI: R
1=R
2=R
3=OH, R
4=(CH
2)
2CH
3, 17-propyl group-androstane-3 β, 5 α, 6 beta-triols;
XII: R
1=R
2=R
3=OH, R
4=CH (CH
3)
2, 17-sec.-propyl-androstane-3 β, 5 α, 6 beta-triols;
X III: R
1=R
2=R
3=OH, R
4=CH (CH
2)
3CH
3, 17-butyl-androstane-3 β, 5 α, 6 beta-triols.
3 β provided by the invention, 5 α, the synthetic method of 6 β-trihydroxy-steroid compound is take dehydroepiandros-sterone as raw material, to get 3-O-t-Butyldimethylsilyl-dehydroepiandros-sterone by 3 hydroxyls of TERT-BUTYL DIMETHYL CHLORO SILANE protection; Get 3-O-t-Butyldimethylsilyl-5-alkene-androstane-17-alcohol through sodium borohydride reduction; White solid chemical compounds I again methylates 3-O-t-Butyldimethylsilyl-5-alkene-androstane-17-alcohol to get; The white solid chemical compounds I gets compound 17-methoxyl group dehydroepiandros-sterone through the hydrofluoric acid deprotection; 17-methoxyl group dehydroepiandros-sterone gets compound ii through epoxidation; Compound ii open loop under acidic conditions gets the compound III; Take dehydroepiandros-sterone as raw material, get 3 β through epoxidation, acidic conditions open loop, 5 α, 6 β-trihydroxy-dehydroepiandros-sterone; Vitarrine gets 3 β through epoxidation, acidic conditions open loop, 5 α, 6 β-trihydroxy-Vitarrine; 3 β, 5 α, 6 β-trihydroxy-dehydroepiandros-sterone and 3 β, 5 α, 6 β-trihydroxy-Vitarrine is through obtaining compounds Ⅳ-VIII with wittig reagent iodo-methyl triphenyl phosphorus, bromoethyl triphenyl phosphorus, bromo propyl group triphenyl phosphorus, bromo butyl triphenyl phosphorus reaction; Compounds Ⅳ-VIII gets compound IX-X III through hydro-reduction respectively.
Further, 3 β provided by the invention, 5 α, the concrete reactions steps of the synthetic method of 6 β-trihydroxy-steroid compound is:
(1) take dehydroepiandros-sterone as raw material, be prepared into 3-O-t-Butyldimethylsilyl-dehydroepiandros-sterone by 3 hydroxyls of TERT-BUTYL DIMETHYL CHLORO SILANE protection, 3-O-t-Butyldimethylsilyl-dehydroepiandros-sterone gets 3-O-t-Butyldimethylsilyl-5-alkene-androstane-17-alcohol through sodium borohydride reduction;
(2) compound 3-O-t-Butyldimethylsilyl-5-alkene-androstane-17-alcohol is dissolved in anhydrous solvent, logical protection gas adds NaH, and airtight, room temperature reaction injects CH after for some time
3I continues to stir, and reaction solution is distributed in the frozen water, transfers pH to neutral, extraction, and drying, concentrating under reduced pressure, acetone recrystallization gets the white solid chemical compounds I;
(3) the white solid chemical compounds I is dissolved in the methylene dichloride through hydrofluoric acid deprotection gained compound 17-methoxyl group dehydroepiandros-sterone, add entry and anhydrous sodium carbonate, stir into emulsion after, add metachloroperbenzoic acid in batches, react under the room temperature, when the TLC tracking monitor is complete to the raw material primitive reaction, add saturated sodium bisulfite solution cancellation reaction, standing demix, water solvent extraction, be washed till neutrality, drying, the concentrated faint yellow solid that obtains, the silica gel column chromatography compound ii of purifying to get;
(4) compound ii is dissolved in the solvent, adds sulfuric acid, stirring reaction under the room temperature, accent pH is to neutral, and steaming desolventizes, extraction, washing, drying concentrates and obtains white solid, and purification by silica gel column chromatography gets the compound III;
(5) dehydroepiandros-sterone is through epoxidation, and the acidic conditions open loop gets 3 β, 5 α, 6 β-trihydroxy-dehydroepiandros-sterone; Vitarrine is through epoxidation, and the acidic conditions open loop gets 3 β, 5 α, 6 β-trihydroxy-Vitarrine;
(6) the iodo-methyl triphenyl phosphorus is dissolved in the anhydrous solvent, logical protection gas adds potassium tert.-butoxide in batches, sealing, stirring at room is with 3 β, 5 α, the solution of 6 β-trihydroxy-dehydroepiandros-sterone joins in the reaction solution, refluxes for some time behind the first room temperature reaction, cooling, frozen water dilution, extraction, dry, concentrating under reduced pressure, column chromatography is separated, and gets compounds Ⅳ;
(7) the bromoethyl triphenyl phosphorus is dissolved in the anhydrous solvent, logical protection gas adds potassium tert.-butoxide in batches, sealing, stirring at room is with 3 β, 5 α, the solution of 6 β-trihydroxy-dehydroepiandros-sterone joins in the reaction solution, refluxes for some time behind the first room temperature reaction, cooling, frozen water dilution, extraction, dry, concentrating under reduced pressure, column chromatography is separated, and gets the compound V;
(8) bromo propyl group triphenyl phosphorus is dissolved in the anhydrous solvent, logical protection gas adds potassium tert.-butoxide in batches, sealing, stirring at room is with 3 β, 5 α, the solution of 6 β-trihydroxy-dehydroepiandros-sterone joins in the reaction solution, refluxes for some time behind the first room temperature reaction, cooling, frozen water dilution, extraction, dry, concentrating under reduced pressure, column chromatography is separated, and gets the compound VI;
(9) the iodo-methyl triphenyl phosphorus is dissolved in the anhydrous solvent, logical protection gas, sealing is injected n-Butyl Lithium to solution and is clarified; stirring at room for some time, with compound 3 β, 5 α, the solution of 6 β-trihydroxy-Vitarrine joins in the reaction solution; react under the heating condition, cooling adds saturated NH
4Cl solution, extraction, drying, concentrating under reduced pressure, column chromatography is separated, and gets the compound VII;
(10) bromo butyl triphenyl phosphorus is dissolved in the anhydrous solvent, logical protection gas adds potassium tert.-butoxide in batches, sealing, stirring at room is with 3 β, 5 α, the solution of 6 β-trihydroxy-dehydroepiandros-sterone joins in the reaction solution, refluxes for some time behind the first room temperature reaction, cooling, frozen water dilution, extraction, dry, concentrating under reduced pressure, column chromatography is separated, and gets the compound VIII;
(11) compounds Ⅳ is dissolved in the methyl alcohol, add Pd/C, sealing, be hydrogen with the air displacement in the reaction system, under the hydrogen system, react, when the LC-MS tracking monitor is complete to the raw material primitive reaction, finish reaction, remove by filter palladium carbon, the filter cake solvent washing, the evaporated under reduced pressure solvent gets the compound IX;
(12) the compound V is dissolved in the methyl alcohol, add Pd/C, sealing, be hydrogen with the air displacement in the reaction system, under the hydrogen system, react, when the LC-MS tracking monitor is complete to the raw material primitive reaction, finish reaction, remove by filter palladium carbon, the filter cake solvent washing, the evaporated under reduced pressure solvent gets the compound X;
(13) the compound VI is dissolved in the methyl alcohol, add Pd/C, sealing, be hydrogen with the air displacement in the reaction system, under the hydrogen system, react, when the LC-MS tracking monitor is complete to the raw material primitive reaction, finish reaction, remove by filter palladium carbon, the filter cake solvent washing, the evaporated under reduced pressure solvent gets the compound XI;
(14) the compound VII is dissolved in the methyl alcohol, add Pd/C, sealing, be hydrogen with the air displacement in the reaction system, under the hydrogen system, react, when the LC-MS tracking monitor is complete to the raw material primitive reaction, finish reaction, remove by filter palladium carbon, the filter cake solvent washing, the evaporated under reduced pressure solvent gets the compound XII;
(15) the compound VIII is dissolved in the methyl alcohol, add Pd/C, sealing, be hydrogen with the air displacement in the reaction system, under the hydrogen system, react, when the LC-MS tracking monitor is complete to the raw material primitive reaction, finish reaction, remove by filter palladium carbon, the filter cake solvent washing, the evaporated under reduced pressure solvent gets compound X III.
In the above-mentioned concrete reactions steps:
Anhydrous solvent is THF in the step (2); Protection gas is nitrogen or argon gas; 3-O-t-Butyldimethylsilyl-5-alkene-androstane-17-alcohol, NaH and CH
3The mol ratio of I is 1 ︰, 3 ~ 6 ︰ 3 ~ 6; Adding the post-reacted time of NaH is 20min-60min; Inject CH
3Room temperature reaction 8 ~ 24 h behind the I.
The amount ratio of 17-methoxyl group dehydroepiandros-sterone, methylene dichloride and water is 1g ︰ 20 ~ 40mL ︰ 40 ~ 60mL in the step (3); The mol ratio of 17-methoxyl group dehydroepiandros-sterone, yellow soda ash and metachloroperbenzoic acid is 1 ︰, 2.5 ~ 4 ︰ 1.2 ~ 1.6.
Solvent in the step (4) is acetone; Sulfuric acid is 1N-3N sulfuric acid; Reaction times is 20 ~ 48h.
Anhydrous solvent is THF or DMSO in step (6-8) and the step (10); Protection gas is nitrogen or argon gas; 3 β, 5 α, the mol ratio of 6 β-trihydroxy-dehydroepiandros-sterone, wittig reagent and potassium tert.-butoxide is 1 ︰, 2 ~ 4 ︰ 2 ~ 4; Reaction times is room temperature reaction 2 ~ 8 h, back flow reaction 2 ~ 5 h.
Anhydrous solvent is THF in the step (9), and protection gas is nitrogen or argon gas; 3 β, 5 α, the mol ratio of 6 β-trihydroxy-Vitarrine, wittig reagent and n-Butyl Lithium is 1 ︰, 2 ~ 4 ︰ 8 ~ 12; Reaction times is room temperature reaction 3 ~ 6 h, 60 ℃ of reaction 2 ~ 8 h.
The amount ratio of compounds Ⅳ-VIII, Pd/C is 1g ︰ 100 ~ 300mg in the step (11-15), reacts 12 ~ 48 h under the hydrogen system.
3 β provided by the invention; 5 α; it is cheap and easy to get that the synthetic method of 6 β-trihydroxy-steroid compound has raw material; reaction conditions is gentle; simple to operate, the characteristics such as synthetic route is short, 3 synthetic β; 5 α, 6 β-trihydroxy-steroid compound can be applicable to the cerebellar granule neuron excitotoxic injury for preparing glutamate induction to have in the medicine of provide protection.The applicant observes the neurocyte form with the cerebellar granule neuron excitotoxic injury model of glutamate induction with phase microscope; With FDA dyeing, measure the activity of respectively organizing lactic acid and lactalase, study 3 β, 5 α, the neuroprotective of 6 β-trihydroxy steroid compounds.Found that 3 β, 5 α, 6 β-trihydroxy steroid compounds VI: 17-propylidene-androstane-3 β, 5 α, 6 beta-triols; XII: 17-butyl-androstane-3 β, 5 α, 6 beta-triols; X III 17-methoxyl group-androstane-3 β, 5 α, the most of cerebellar granule neuron of 6 beta-triols+L-glutamic acid group and MK801+ L-glutamic acid group can keep the complete of cell space and projection, cell survival rate increases, the LDH releasing value reduces, and relatively presents notable difference with the L-glutamic acid group, and 3 β, 5 α, there is the concentration dependence in 6 β-trihydroxy-steroidal.
Description of drawings
Fig. 1 is 3 β, 5 α, and 6 β-trihydroxy steroid compounds VI is to the phase microscope photo of the provide protection of the cerebellar granule neuron excitotoxic injury of glutamate induction;
Fig. 2 is 3 β, 5 α, and (* and * * represent respectively to compare with the control group and have difference, * 6 β-trihydroxy steroid compounds VI to the LDH releasing value of the provide protection of the cerebellar granule neuron excitotoxic injury of glutamate induction
P＜0.05, * *
P＜0.01);
Fig. 3 is 3 β, 5 α, and 6 β-trihydroxy steroid compounds XII is to the phase microscope photo of the provide protection of the cerebellar granule neuron excitotoxic injury of glutamate induction;
Fig. 4 is 3 β, 5 α, and (* and * * represent respectively to compare with the control group and have difference, * 6 β-trihydroxy steroid compounds XII to the LDH releasing value of the provide protection of the cerebellar granule neuron excitotoxic injury of glutamate induction
P＜0.05, * *
P＜0.01);
Fig. 5 is 3 β, 5 α, and 6 β-trihydroxy steroid compounds X III is to the phase microscope photo of the provide protection of the cerebellar granule neuron excitotoxic injury of glutamate induction;
Fig. 6 is 3 β, 5 α, and (* and * * represent respectively to compare with the control group and have difference, * 6 β-trihydroxy steroid compounds X III to the LDH releasing value of the provide protection of the cerebellar granule neuron excitotoxic injury of glutamate induction
P＜0.05, * *
P＜0.01).
Embodiment
One,3 β, 5 α, 6 β-trihydroxy steroid compounds synthetic
Following examples only are used for setting forth the present invention, and protection scope of the present invention is not only to be confined to following examples, and the those of ordinary skill of described technical field all can be realized purpose of the present invention according to above content disclosed by the invention and scope that each parameter is got.In following examples: I: 3-O-t-Butyldimethylsilyl-17-methoxyl group dehydroepiandros-sterone; II: 5 α, 6 alpha-epoxy-17s-methoxyl group-dehydroepiandros-sterone; III: 17-methoxyl group-androstane-3 β, 5 α, 6 beta-triols; IV: 17-methylene radical-androstane-3 β, 5 α, 6 beta-triols; V: 17-ethylidene-androstane-3 β, 5 α, 6 beta-triols; VI: 17-propylidene-androstane-3 β, 5 α, 6 beta-triols; VII: 17-pseudoallyl-androstane-3 β, 5 α, 6 beta-triols; VIII: 17-butylidene-androstane-3 β, 5 α, 6 beta-triols; IX: 17-methyl-androstane-3 β, 5 α, 6 beta-triols; X: 17-ethyl-androstane-3 β, 5 α, 6 beta-triols; XI: 17-propyl group-androstane-3 β, 5 α, 6 beta-triols; XII: 17-sec.-propyl-androstane-3 β, 5 α, 6 beta-triols; X III: 17-butyl-androstane-3 β, 5 α, 6 beta-triols.
The synthetic method of chemical compounds I ~ III that embodiment 1 provides comprises the steps:
(1) take dehydroepiandros-sterone as raw material, be prepared into 3-O-t-Butyldimethylsilyl-dehydroepiandros-sterone by 3 hydroxyls of TERT-BUTYL DIMETHYL CHLORO SILANE protection, get 3-O-t-Butyldimethylsilyl-5-alkene-androstane-17-alcohol through sodium borohydride reduction.
(2) compound 3-O-t-Butyldimethylsilyl-5-alkene-androstane-17-alcohol 8.8g (21.8mmol) is dissolved in anhydrous THF160mL, N
2Protection adds NaH (2.56g, 0.11 mol), and is airtight, injects CH behind the room temperature reaction 30min
3I (6.74mL, 0.11mol), stirring is spent the night.Reaction solution is distributed in the frozen water (400mL), and acetic acid transfers pH to neutral, ethyl acetate extraction 3 times, anhydrous Na
2SO
4Drying, concentrating under reduced pressure, acetone recrystallization gets white solid chemical compounds I 8.78 g.
(3) hydrofluoric acid 2.5 mL are slowly splashed in the methylene dichloride 40mL solution of chemical compounds I 4.4 g (8mmol) stirring at room 20 h.Reaction solution is distributed among the frozen water 250mL, dichloromethane extraction three times, anhydrous Na
2SO
4Drying, concentrating under reduced pressure gets white solid compound 17-methoxyl group dehydroepiandros-sterone 3.39 g.
(4) the hydrofluoric acid deprotection gained compound 17-methoxyl group dehydroepiandros-sterone (3g that learns from else's experience; 9.9 mmol) be dissolved in the methylene dichloride (30mL); add 60mL water; anhydrous sodium carbonate (3.18g; 30mmol); after stirring into emulsion, add 80% metachloroperbenzoic acid, 3.24 g (15mmol) in batches, react 6h under the room temperature.When the TLC tracking monitor is complete to the raw material primitive reaction, add saturated sodium bisulfite solution 50mL cancellation reaction, standing demix, water dichloromethane extraction 3 times, merge organic phase, be washed to neutrality with saturated common salt, anhydrous sodium sulfate drying, the concentrated 2.9 g faint yellow solids that obtain.Silica gel column chromatography (ethyl acetate: sherwood oil, V:V=1:4) white solid compound ii 2.7 g that purify to get.
(5) get compound ii (2 g, 6.2 mmol) and be dissolved among acetone 40 mL, add sulfuric acid (1N 40mL), stirring reaction 48h under the room temperature.Reaction finishes rear extremely neutral with saturated sodium bicarbonate accent pH, revolves to boil off most of acetone, adds ethyl acetate extraction, and the organic phase of merging washes with water, anhydrous sodium sulfate drying, the concentrated white solid that obtains.(acetone: sherwood oil, V:V=1:1) purifying gets white solid III 2.11g to silica gel column chromatography.
Embodiment 2
The synthetic method of compounds Ⅳ ~ VIII that embodiment 2 provides comprises the steps:
(1) iodo-methyl triphenyl phosphorus 15g (36mmol) is dissolved among the anhydrous THF of 100mL N
2Protection; add 4.2g potassium tert.-butoxide (36mmol) in batches; sealing; stirring at room l h; with syringe with compound 3 β, 5 α, DMSO (50mL) solution of 6 β-trihydroxy-dehydroepiandros-sterone 4.05 g (12.0mmol) joins in the reaction solution; room temperature reaction 6h, back flow reaction 3h.Cooling, frozen water 200mL dilution, ethyl acetate 600mL extraction, organic solvent water 300mL and saturated aqueous common salt 300mL washing 3 times, anhydrous Na
2SO
4Drying, concentrating under reduced pressure, (acetone: sherwood oil V:V=1:4), gets the 3.6g compounds Ⅳ in the column chromatography separation.
(2) synthetic method of compound V is except replacing the iodo-methyl triphenyl phosphorus with the bromoethyl triphenyl phosphorus, other and embodiment 2.(1) basic identical, get 3.86 g products.
(3) generative process of compound VI is except replacing the iodo-methyl triphenyl phosphorus with bromo propyl group triphenyl phosphorus, other and embodiment 2.(1) basic identical, get the 4.10g product.
(4) generative process of compound VIII is except replacing the iodo-methyl triphenyl phosphorus with bromo butyl triphenyl phosphorus, other and embodiment 2.(1) basic identical, get the 4.10g product.
(5) iodo-methyl triphenyl phosphorus 7.5g (18mmol) is dissolved among the anhydrous THF (100mL) N
2Protection, sealing is injected n-Butyl Lithium to solution and is clarified; about 12mL (0.15mol), stirring at room 4 h are with compound 3 β; 5 α, the THF solution of the 30mL of 6 β-trihydroxy-dehydroepiandros-sterone 2.1g (6.0mmol) joins in the reaction solution, 60 ℃ of reaction 3h.Cooling adds saturated NH
4Cl solution is to layering, approximately 50mL.Lower floor's ethyl acetate extraction three times merge organic phase, anhydrous Na
2SO
4Drying, concentrating under reduced pressure, (acetone: sherwood oil V:V=1:4), gets 3.6g product compound VII in the column chromatography separation.
Embodiment 3
The synthetic method of the compound IX that embodiment 3 provides ~ X III comprises the steps:
(1) compounds Ⅳ (2.19 g, 6.8mmol) is dissolved in the 50mL methyl alcohol, adds 10% Pd/C 0.66g, sealing is hydrogen with the air displacement in the reaction system, and reaction is reaction 24 h under hydrogen stream.Finish reaction when the LC-MS tracking monitor is complete to the raw material primitive reaction, removes by filter palladium carbon, filter cake washes with ethyl acetate 200mL, and the evaporated under reduced pressure solvent gets 2.1g sample compound IX.
(2) synthetic method of compound X and embodiment 3.(1) basic identical.V (2.5g, 7.5 mmol) is dissolved among the methyl alcohol 55mL, adds 10% Pd/C 0.75g, get sample 2.4g.
(3) synthetic method of compound XI and embodiment 3.(1) basic identical.VI (0.83g, 2 mmol) is dissolved among the methyl alcohol 25mL, adds 10% Pd/C 0.25g, get sample 0.70g.
(4) synthetic method of compound XII and embodiment 3.(1) basic identical.VII (2g, 5.5 mmol) is dissolved among the methyl alcohol 50mL, adds 10% Pd/C 0.60g, get sample 1.9g.
(5) synthetic method of compound X III and embodiment 3.(1) basic identical.VIII (0.85g, 2.4mmol) is dissolved among the methyl alcohol 25mL, adds 10% Pd/C 0.26g, get sample 0.81g.
Embodiment 4
The synthetic method of chemical compounds I ~ III that embodiment 4 provides comprises the steps:
(1) chemical compounds I is synthetic identical with step (1) ~ (2) among the embodiment 1.
(2) hydrofluoric acid 2.5 mL are slowly splashed in the methylene dichloride 40mL solution of chemical compounds I 4.4 g (8mmol) stirring at room 20 h.Reaction solution is distributed among the frozen water 250mL, dichloromethane extraction three times, anhydrous Na
2SO
4Drying, concentrating under reduced pressure gets white solid compound 17-methoxyl group dehydroepiandros-sterone 3.39 g.
(3) the hydrofluoric acid deprotection gained compound 17-methoxyl group dehydroepiandros-sterone (3g that learns from else's experience; 9.9 mmol) be dissolved in the methylene dichloride (50mL); add 50mL water; anhydrous sodium carbonate (2.76g; 26mmol); after stirring into emulsion; add 80% metachloroperbenzoic acid, 2.78 g (13mmol) in batches; add saturated sodium bisulfite solution 50mL cancellation reaction, standing demix, water dichloromethane extraction 3 times under the room temperature behind the reaction 12h; merge organic phase; be washed to neutrality, anhydrous sodium sulfate drying, the concentrated 2.84g faint yellow solid that obtains.Silica gel column chromatography (ethyl acetate: sherwood oil, V:V=1:4) the white solid compound ii 2.6g that purifies to get.
(4) get compound ii (2g, 6.2 mmol) and be dissolved among acetone 40 mL, add sulfuric acid (2N 25mL), stirring reaction 24h under the room temperature.Reaction finishes rear extremely neutral with saturated sodium bicarbonate accent pH, revolves to boil off most of acetone, adds ethyl acetate extraction, and the organic phase of merging washes with water, anhydrous sodium sulfate drying, the concentrated white solid that obtains.(acetone: sherwood oil, V:V=1:1) purifying gets white solid III 2.0g to silica gel column chromatography.
The synthetic method of compounds Ⅳ ~ VIII that embodiment 5 provides comprises the steps:
(1) iodo-methyl triphenyl phosphorus 10g (24mmol) is dissolved among the anhydrous THF of 100mL N
2Protection; add 2.8g potassium tert.-butoxide (24mmol) in batches; sealing; stirring at room 2h; with syringe with compound 3 β, 5 α, DMSO (50mL) solution of 6 β-trihydroxy-dehydroepiandros-sterone 4.05 g (12.0mmol) joins in the reaction solution; room temperature reaction 3h, back flow reaction 5h.Cooling, frozen water 200mL dilution, ethyl acetate 500mL extraction, organic solvent water 300mL washing 3 times, anhydrous Na
2SO
4Drying, concentrating under reduced pressure, (acetone: sherwood oil V:V=1:4), gets the 3.5g compounds Ⅳ in the column chromatography separation.
(2) compound V
,VI
,VIII is identical with step (2) ~ (4) among the embodiment 2.
(3) iodo-methyl triphenyl phosphorus 7.5g (18mmol) is dissolved among the anhydrous THF (100mL); argon shield; sealing; inject n-Butyl Lithium to solution and clarify, about 12mL (0.15mol), stirring at room 6 h; with compound 3 β; 5 α, the THF solution of the 30mL of 6 β-trihydroxy-dehydroepiandros-sterone 2.1g (6.0mmol) joins in the reaction solution, 60 ℃ of reaction 4h.Cooling adds saturated NH
4Cl solution is to layering, approximately 50mL.Lower floor's ethyl acetate extraction three times merge organic phase, anhydrous Na
2SO
4Drying, concentrating under reduced pressure, (acetone: sherwood oil V:V=1:4), gets 3.6g product compound VII in the column chromatography separation.
Embodiment 6
The synthetic method of the compound IX that embodiment 6 provides ~ X III comprises the steps:
(1) compounds Ⅳ (2.19 g, 6.8mmol) is dissolved in the 50mL methyl alcohol, adds 10% Pd/C 0.50g, sealing is hydrogen with the air displacement in the reaction system, and reaction is reacted 36h under hydrogen stream.Finish reaction when the LC-MS tracking monitor is complete to the raw material primitive reaction, removes by filter palladium carbon, filter cake washes with ethyl acetate 200mL, and the evaporated under reduced pressure solvent gets 2.1g sample compound IX.
(2) compound X ~ X III is identical with step (2) ~ (5) among the embodiment 3.
Embodiment 7
The synthetic method of chemical compounds I ~ III that embodiment 7 provides comprises the steps:
(1) take dehydroepiandros-sterone as raw material, be prepared into 3-O-t-Butyldimethylsilyl-dehydroepiandros-sterone by 3 hydroxyls of TERT-BUTYL DIMETHYL CHLORO SILANE protection, get 3-O-t-Butyldimethylsilyl-5-alkene-androstane-17-alcohol through sodium borohydride reduction.
(2) compound 3-O-t-Butyldimethylsilyl-5-alkene-androstane-17-alcohol 8.8g (21.8mmol) is dissolved in anhydrous THF160mL, argon shield adds NaH (2.56g, 0.11 mol), and is airtight, injects CH behind the room temperature reaction 40min
3I (6.74mL, 0.11mol) stirs 12 h.Reaction solution is distributed in the frozen water (400mL), and acetic acid transfers pH to neutral, ethyl acetate extraction 3 times, anhydrous Na
2SO
4Drying, concentrating under reduced pressure, acetone recrystallization gets white solid chemical compounds I 8.78g.
(3) hydrofluoric acid 2.5 mL are slowly splashed in the methylene dichloride 40mL solution of chemical compounds I 4.4 g (8mmol) stirring at room 20h.Reaction solution is distributed among the frozen water 250mL, dichloromethane extraction three times, anhydrous Na
2SO
4Drying, concentrating under reduced pressure gets white solid compound compound 17-methoxyl group dehydroepiandros-sterone 3.39 g.
(4) the hydrofluoric acid deprotection gained compound 17-methoxyl group dehydroepiandros-sterone (3g that learns from else's experience; 9.9 mmol) be dissolved in the methylene dichloride (40mL); add 50mL water; anhydrous sodium carbonate (2.97g; 28mmol); after stirring into emulsion, add 80% metachloroperbenzoic acid, 3.02 g (14mmol) in batches, react 8h under the room temperature.When the TLC tracking monitor is complete to the raw material primitive reaction, add saturated sodium bisulfite solution 50mL cancellation reaction, standing demix, water dichloromethane extraction 3 times, merge organic phase, be washed to neutrality with saturated common salt, anhydrous sodium sulfate drying, the concentrated 2.84g faint yellow solid that obtains.Silica gel column chromatography (ethyl acetate: sherwood oil, V:V=1:4) white solid compound ii 2.7 g that purify to get.
(5) step (4) compound III synthetic identical among compound III and the embodiment 4.
Embodiment 8
The synthetic method of the compounds Ⅳ ~ VIII that provides that embodiment 8 provides comprises the steps:
(1) iodo-methyl triphenyl phosphorus 20g (48mmol) is dissolved among the anhydrous THF of 100mL N
2Protection; add 5.6g potassium tert.-butoxide (48mmol) in batches; sealing; stirring at room l h; with syringe with compound 3 β, 5 α, DMSO (50mL) solution of 6 β-trihydroxy-dehydroepiandros-sterone 4.05 g (12.0mmol) joins in the reaction solution; room temperature reaction 12h, back flow reaction 4h.Cooling, frozen water 200mL dilution, ethyl acetate 600mL extraction, organic solvent water 400mL washing 3 times, anhydrous Na
2SO
4Drying, concentrating under reduced pressure, (acetone: sherwood oil V:V=1:4), gets the 3.7g compounds Ⅳ in the column chromatography separation.
(2) synthetic method of compound V is except replacing the iodo-methyl triphenyl phosphorus with the bromoethyl triphenyl phosphorus, other and embodiment 8.(1) basic identical, get 3.9 g products.
(3) generative process of compound VI is except replacing the iodo-methyl triphenyl phosphorus with bromo propyl group triphenyl phosphorus, other and embodiment 8.(1) basic identical, get the 4.14g product.
(4) generative process of compound VIII is except replacing the iodo-methyl triphenyl phosphorus with bromo butyl triphenyl phosphorus, other and embodiment 8.(1) basic identical, get the 4.12g product.
(5) step (3) compound VII synthetic identical among compound VII and the embodiment 5.
Embodiment 9
The synthetic method of the compound IX that embodiment 9 provides ~ X III comprises the steps:
(1) compounds Ⅳ (2.19 g, 6.8mmol) is dissolved in the 45mL methyl alcohol, adds 10% Pd/C 0.58g, sealing is hydrogen with the air displacement in the reaction system, and reaction is reacted 24h under hydrogen stream.Finish reaction when the LC-MS tracking monitor is complete to the raw material primitive reaction, removes by filter palladium carbon, filter cake washes with ethyl acetate 200mL, and the evaporated under reduced pressure solvent gets 2.1g sample compound IX.
(2) synthetic method of compound X and embodiment 9.(1) basic identical.V (2.5g, 7.5 mmol) is dissolved among the methyl alcohol 55mL, adds 10% Pd/C 0.66g, get sample 2.35g.
(3) synthetic method of compound XI and embodiment 9.(1) basic identical.VI (0.83g, 2 mmol) is dissolved among the methyl alcohol 25mL, adds 10% Pd/C 0.22 g, get sample 0.68 g.
(4) synthetic method of compound XII and embodiment 9.(1) basic identical.VII (2g, 5.5 mmol) is dissolved among the methyl alcohol 50mL, adds 10% Pd/C 0.55g, get sample 1.86g.
(5) synthetic method of compound X III and embodiment 9.(1) basic identical.VIII (0.85g, 2.4mmol) is dissolved among the methyl alcohol 25mL, adds 10% Pd/C 0.22g, get sample 0.80g.
Two, 3 β, 5 α, the research of the neuroprotective of 6 β-trihydroxy steroid compounds
Take out and give birth to 7 ~ 8d, body weight is the removal meninx of 15 ~ 20g rat and the cerebellum of blood vessel approximately, after 0.25 g/L trysinization, the liquid that dispels with 0.05 g/L DNase I dispels cell and is single cell suspension, centrifugal, get precipitation, usefulness contains the BME substratum dilution of 10% (v/v) FBS and 25 mM KCl and is inoculated in the pre-coated culture dish of poly-lysine.Inoculate after 24 hours and to add 10 μ M Ara-C to suppress growth and the propagation of non-neuronal cell, make the purity of cerebellar granule neuron more than 95%.Add glucose during cultivation and replenish cellular metabolism institute energy requirement.Tested in the 8th day.
Embodiment 2 provides 3 β, 5 α, and 6 β-trihydroxy steroid compounds is to the provide protection of former culture neuronal cell
Cultivate 8 days cerebellar granule neuron, establish respectively Normal group, L-glutamic acid group, MK801+ L-glutamic acid, 3 β, 5 α, 6 β-trihydroxy steroid compounds+L-glutamic acid group.Normal group is left intact, and the L-glutamic acid group adds 200 μ M L-glutamic acid, and other group adds MK801(10 μ M in advance) and 3 β of different concns, 5 α, 6 β-trihydroxy steroid compounds are hatched after 30 minutes for 37 ℃ and are added L-glutamic acid, behind 24 h with phase microscope neurocyte form; With FDA dyeing, inverted fluorescence microscope is observed.And mensuration is respectively organized the activity of lactic acid and lactalase.
Found that 3 β, 5 α, 6 β-trihydroxy steroid compounds VI: 17-propylidene-androstane-3 β, 5 α, 6 beta-triols; XII: 17-sec.-propyl-androstane-3 β, 5 α, 6 beta-triols; X III: 17-butyl-androstane-3 β, 5 α, the most of cerebellar granule neuron of 6 beta-triols+L-glutamic acid group and MK801+ L-glutamic acid group can keep the complete of cell space and projection, cell survival rate increases, and the LDH releasing value reduces, and relatively presents notable difference with the L-glutamic acid group, and 3 β, 5 α, there is the concentration dependence in 6 β-trihydroxy-steroidal, sees Fig. 1-6.
Claims (8)
1.3 β, 5 α, 6 β-trihydroxy-steroid compound is characterized in that, have following structure:
Ⅵ、Ⅻ、ⅩⅢ
Described compound VI, XII, X III be respectively,
VI: R
1=R
2=R
3=OH, R
4=CH CH
2CH
3, 17-propylidene-androstane-3 β, 5 α, 6 beta-triols;
XII: R
1=R
2=R
3=OH, R
4=CH (CH
3)
2, 17-sec.-propyl-androstane-3 β, 5 α, 6 beta-triols;
X III: R
1=R
2=R
3=OH, R
4=(CH
2)
3CH
3, 17-butyl-androstane-3 β, 5 α, 6 beta-triols.
2. 3 β claimed in claim 1,5 α, the synthetic method of 6 β-trihydroxy-steroid compound is characterized in that, concrete reactions steps is:
(1) dehydroepiandros-sterone is through epoxidation, and the acidic conditions open loop gets 3 β, 5 α, 6 β-trihydroxy-dehydroepiandros-sterone; Vitarrine is through epoxidation, and the acidic conditions open loop gets 3 β, 5 α, 6 β-trihydroxy-Vitarrine;
(2) bromo propyl group triphenyl phosphorus is dissolved in the anhydrous solvent, logical protection gas adds potassium tert.-butoxide in batches, sealing, stirring at room is with 3 β, 5 α, the solution of 6 β-trihydroxy-dehydroepiandros-sterone joins in the reaction solution, refluxes for some time behind the first room temperature reaction, cooling, frozen water dilution, extraction, drying, concentrating under reduced pressure, column chromatography is separated, get the compound VI: 17-propylidene-androstane-3 β, 5 α, 6 beta-triols;
(3) the iodo-methyl triphenyl phosphorus is dissolved in the anhydrous solvent, logical protection gas, sealing is injected n-Butyl Lithium to solution and is clarified; stirring at room for some time, with compound 3 β, 5 α, the solution of 6 β-trihydroxy-Vitarrine joins in the reaction solution; react under the heating condition, cooling adds saturated NH
4Cl solution, extraction, drying, concentrating under reduced pressure, column chromatography is separated, and gets the compound VII: 17-pseudoallyl-androstane-3 β, 5 α, 6 beta-triols;
(4) the compound VII is dissolved in the methyl alcohol, add Pd/C, sealing is hydrogen with the air displacement in the reaction system, under the hydrogen system, react, when the LC-MS tracking monitor is complete to the raw material primitive reaction, finish reaction, remove by filter palladium carbon, the filter cake solvent washing, the evaporated under reduced pressure solvent, get the compound XII: 17-sec.-propyl-androstane-3 β, 5 α, 6 beta-triols;
(5) bromo butyl triphenyl phosphorus is dissolved in the anhydrous solvent, logical protection gas adds potassium tert.-butoxide in batches, sealing, stirring at room is with 3 β, 5 α, the solution of 6 β-trihydroxy-dehydroepiandros-sterone joins in the reaction solution, refluxes for some time behind the first room temperature reaction, cooling, frozen water dilution, extraction, drying, concentrating under reduced pressure, column chromatography is separated, get the compound VIII: 17-butylidene-androstane-3 β, 5 α, 6 beta-triols;
(6) the compound VIII is dissolved in the methyl alcohol, add Pd/C, sealing is hydrogen with the air displacement in the reaction system, under the hydrogen system, react, when the LC-MS tracking monitor is complete to the raw material primitive reaction, finish reaction, remove by filter palladium carbon, the filter cake solvent washing, the evaporated under reduced pressure solvent, get compound X III: 17-butyl-androstane-3 β, 5 α, 6 beta-triols.
3. 3 β according to claim 2,5 α, the synthetic method of 6 β-trihydroxy-steroid compound is characterized in that, anhydrous solvent is THF or DMSO in the step (2); Protection gas is nitrogen or argon gas; 3 β, 5 α, the mol ratio of 6 β-trihydroxy-dehydroepiandros-sterone, bromo propyl group triphenyl phosphorus and potassium tert.-butoxide is 1 ︰, 2 ~ 4 ︰ 2 ~ 4; Reaction times is room temperature reaction 2 ~ 8 h, back flow reaction 2 ~ 5 h.
4. 3 β according to claim 2,5 α, the synthetic method of 6 β-trihydroxy-steroid compound is characterized in that, and anhydrous solvent is THF in the step (3), and protection gas is nitrogen or argon gas; 3 β, 5 α, the mol ratio of 6 β-trihydroxy-Vitarrine, iodo-methyl triphenyl phosphorus and n-Butyl Lithium is 1 ︰, 2 ~ 4 ︰ 8 ~ 12; Reaction times is room temperature reaction 3 ~ 6 h, 60 ℃ of reaction 2 ~ 8 h.
5. 3 β according to claim 2,5 α, the synthetic method of 6 β-trihydroxy-steroid compound is characterized in that, anhydrous solvent is THF or DMSO in the step (5); Protection gas is nitrogen or argon gas; 3 β, 5 α, the mol ratio of 6 β-trihydroxy-dehydroepiandros-sterone, bromo butyl triphenyl phosphorus and potassium tert.-butoxide is 1 ︰, 2 ~ 4 ︰ 2 ~ 4; Reaction times is room temperature reaction 2 ~ 8 h, back flow reaction 2 ~ 5 h.
6. 3 β according to claim 2,5 α, the synthetic method of 6 β-trihydroxy-steroid compound is characterized in that, the amount ratio of compound VII, Pd/C is 1g ︰ 100 ~ 300mg in the step (4), reacts 12 ~ 48 h under the hydrogen system.
7. 3 β according to claim 2,5 α, the synthetic method of 6 β-trihydroxy-steroid compound is characterized in that, the amount ratio of compound VIII, Pd/C is 1g ︰ 100 ~ 300mg in the step (6), reacts 12 ~ 48 h under the hydrogen system.
8. 3 β claimed in claim 1,5 α, 6 β-trihydroxy-steroid compound VI, XII, X III have application in the medicine of provide protection in preparation to the cerebellar granule neuron excitotoxic injury of glutamate induction.
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| CN109985049B (en) * | 2017-12-29 | 2022-02-22 | 广州市赛普特医药科技股份有限公司 | Application of 5 alpha-androstane-3 beta, 5,6 beta-triol in preparing medicine for treating cerebral small vessel disease |
| CN113350359B (en) | 2017-12-29 | 2022-08-16 | 广州市赛普特医药科技股份有限公司 | Application of 5 alpha-androstane-3 beta, 5,6 beta-triol in preparation of medicine for treating hemorrhagic stroke |
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