CN104529967A - Preparation method for lingzhiol - Google Patents

Preparation method for lingzhiol Download PDF

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CN104529967A
CN104529967A CN201410746625.2A CN201410746625A CN104529967A CN 104529967 A CN104529967 A CN 104529967A CN 201410746625 A CN201410746625 A CN 201410746625A CN 104529967 A CN104529967 A CN 104529967A
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compound
reaction
organic solvent
structural formula
cancellation
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CN104529967B (en
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黄�俊
龙榕
邵文斌
龚建贤
杨震
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Peking University Shenzhen Graduate School
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Peking University Shenzhen Graduate School
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered

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Abstract

A preparation method for lingzhiol comprises the following steps: mixing a compound A with the structural formula shown in the specification with a first catalyst in a first organic solvent, and performing thermal-insulation reaction at 85 DEG C in CO atmosphere, so as to obtain a compound B; mixing the compound B with sodium borohydride and performing reduction reaction, so as to obtain a compound C; performing allylic oxidation on the compound C and selenium dioxide, so as to obtain a compound D; mixing the compound D with a second catalyst in a third organic solvent, and performing catalytic hydrogenation reaction, so as to obtain a compound E; performing benzylic oxidation reaction on the compound E, benzoyl peroxide and N-bromosuccinimide, and then adding an oxidant and reacting, so as to obtain a compound F; and performing thermal-insulation reaction on the compound F, 2-methyl-2-propanethiol and aluminium trichloride at 40 DEG C, so as to obtain lingzhiol. Lingzhiol prepared by employing the above preparation method for lingzhiol makes up deficiency of naturally-extracted lingzhiol.

Description

The preparation method of glossy ganoderma alcohol
Technical field
The present invention relates to pharmaceutical synthesis field, particularly relate to a kind of preparation method of glossy ganoderma alcohol.
Background technology
Lingzhiol (glossy ganoderma alcohol) is taught by Cheng Yongxian to separate from Chinese traditional Chinese medicine glossy ganoderma (be the sporophore of On Polyporaceae glossy ganoderma, formal name used at school is Ganoderma lucidum) in 2013 with his co-worker.
Lingzhiol has the good biological activity of selectivity, is shown by biological experiment, first suppresses phosphorylation in it at mouse liver epithelial cells express, thus stimulation of renal Tubular epithelial cell and cure ephritis; Then in Mice Body, show activation mesangial cell, thus play the cytoactive of resisting tumour and diabetes.But existing Lingzhiol extracts from the plants such as glossy ganoderma, limited amount, the demand of people to glossy ganoderma alcohol can not be met.
Summary of the invention
Given this, be necessary the preparation method that a kind of glossy ganoderma alcohol is provided, to make up the deficiency of natural glossy ganoderma alcohol, thus meet the demand of people to glossy ganoderma alcohol.
A preparation method for glossy ganoderma alcohol, comprises the steps:
At anhydrous condition, by structural formula be compd A mix in the first organic solvent with the first catalyzer, 85 DEG C of insulation reaction 20 hours under the atmosphere of carbon monoxide, obtaining structural formula is compd B;
At 0 DEG C, be that 1:10 in alcohol in mix with sodium borohydride according to mol ratio by described compd B, and in 0 DEG C of reduction reaction 1 hour, then through cancellation reaction, obtaining structural formula is compound C;
Be that 1:20 in second organic solvent in mix with tin anhydride according to mol ratio by described Compound C, and carry out allylic oxidation reaction in 110 DEG C, obtaining structural formula is compound D;
Under the atmosphere of hydrogen, described Compound D mixed in the 3rd organic solvent with the second catalyzer, carry out catalytic hydrogenation under room temperature, obtaining structural formula is compd E;
Be that 59:20:71 mixes in the 4th organic solvent by described compd E, benzoyl peroxide and N-bromo-succinimide according to mol ratio, carry out Bian position oxidizing reaction in 80 DEG C, then through cancellation reaction, then add oxygenant, and at room temperature react 24 hours, obtaining structural formula is compound F 17-hydroxy-corticosterone; And
In anhydrous conditions, be that 21:665:280 in five organic solvent in mix by described compound F 17-hydroxy-corticosterone and tert-butyl mercaptan and aluminum chloride according to mol ratio in 0 DEG C, then in 40 DEG C of insulation reaction after 12 hours, through cancellation reaction, obtaining structural formula is glossy ganoderma alcohol.
Wherein in an embodiment, described first catalyzer is four carbonyl diurethane chlorination two rhodiums; Described first organic solvent is anhydrous 1,2-ethylene dichloride.
Wherein in an embodiment, described alcohol is methyl alcohol.
Wherein in an embodiment, described second organic solvent is dioxan.
Wherein in an embodiment, described second catalyzer is the carbon that load has palladium; The mol ratio of described second catalyzer and described Compound D is 1:10; Described 3rd organic solvent is methyl alcohol.
Wherein in an embodiment, described under the atmosphere of hydrogen, described Compound D is mixed in described 3rd organic solvent with described second catalyzer, carry out described catalytic hydrogenation under room temperature, the step obtaining described compd E is specially: described Compound D be dissolved in described 3rd organic solvent, passes into nitrogen to remove oxygen, then described second catalyzer is at room temperature added, then stop passing into nitrogen, and pass into hydrogen, at room temperature react 3 hours.
Wherein in an embodiment, described 4th organic solvent is anhydrous tetracol phenixin; After the step that described compd E, benzoyl peroxide and N-bromo-succinimide are mixed in described 4th organic solvent, before the oxidizing reaction of described Bian position, be also included in the step adding water in mixed described compd E, benzoyl peroxide and N-bromo-succinimide; The described water added and the mass ratio of described compd E are 1:100; Described oxygenant is for wearing this Martin's oxygenant or Manganse Dioxide.
Wherein in an embodiment, described 5th organic solvent is methylene dichloride.
Wherein in an embodiment, in the step of the described compound F 17-hydroxy-corticosterone of preparation, after described cancellation reaction, also comprise the step being carried out by reacted for described cancellation reactant being separated, be specially: reacted for described cancellation reaction solution is extracted with ethyl acetate, obtains organic phase, merge organic phase and drying, through concentrated by rotary evaporation, obtain the crude product be separated; Wherein, described oxygenant is added in described crude product.
Wherein in an embodiment, also comprise the preparation process of described compd A, be specially:
In 0 DEG C, by methyltriphenylphosphonium bromide, tertiary butyl potassium alcoholate and structural formula be compound G mix in the 6th organic solvent, obtain reaction system, described reaction system be warming up to room temperature, and at room temperature react 2 hours, through cancellation reaction, obtaining structural formula is compound H;
Be that 1:1:0.2 mixes in the 7th organic solvent by described compound H, acetic acid iodobenzene and tosic acid according to mol ratio, then add methyl alcohol at 0 DEG C, under room temperature, carry out ring expansion, obtaining structural formula is compound I;
Described Compound I is mixed with formaldehyde, diethylamine hydrochloride and diethylamine in the 8th organic solvent, and carries out methylenation in 105 DEG C, then through cancellation reaction, obtaining structural formula is compound J, wherein, the mol ratio of described formaldehyde, diethylamine hydrochloride and diethylamine is 1:1:1;
At-35 DEG C, described compound J, (R)-2-methyl-CBS-oxazaborolidine-oxazaborolidine and borine are mixed in the 9th organic solvent, and carries out asymmetric carbonyl reduction reaction in-35 DEG C, then through cancellation reaction, obtaining structural formula is compound K;
At 0 DEG C, described compound K is mixed in the tenth organic solvent with sodium hydrogen phosphate, metachloroperbenzoic acid, and carry out oxidizing reaction in 0 DEG C, react through cancellation, obtain reactant, then at 0 DEG C, described reactant is mixed with sodium bicarbonate and Dai Si Martin oxygenant, and carry out oxidizing reaction under room temperature, through cancellation reaction, obtaining structural formula is compound L;
In-78 DEG C, described compound L is mixed with two (trimethyl silicon based) Lithamide and ethyl cyanoformate in the 11 organic solvent, and reacts 2 hours at-78 DEG C, then through cancellation reaction, obtaining structural formula is compound M;
At-20 DEG C, by described compound M and tetrabutyl ammonium fluoride and structural formula be compound R mix in the 12 organic solvent, and at-20 DEG C react 10 hours, through cancellation reaction, obtaining structural formula is compound N;
Described compound N, sodium iodide and trifluoroacetic acid are mixed in the 13 organic solvent at 0 DEG C, and 0 DEG C of reaction 1 hour, be then warming up to room temperature reaction 3 hours, through cancellation reaction, obtaining structural formula is compound P; And
At 0 DEG C, described compound P is mixed with cerous compounds and sodium borohydride in the 14 organic solvent, and carries out reduction reaction in 0 DEG C, through cancellation reaction, obtain described compd A.
The nmr spectrum of the glossy ganoderma alcohol that above-mentioned preparation method prepares conforms to the nmr spectrum of natural glossy ganoderma alcohol, thus natural glossy ganoderma alcohol can be replaced to use, and to make up the deficiency of natural glossy ganoderma alcohol, thus meets the demand of people to glossy ganoderma alcohol.
Accompanying drawing explanation
Fig. 1 is the preparation flow figure of the preparation method of the glossy ganoderma alcohol of an embodiment;
The preparation flow figure of compd A in the preparation method that Fig. 2 is the glossy ganoderma alcohol shown in Fig. 1;
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the Compound I of embodiment 1;
Fig. 4 is the carbon-13 nmr spectra figure of the Compound I of embodiment 1;
Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of the compound J of embodiment 1;
Fig. 6 is the carbon-13 nmr spectra figure of the compound J of embodiment 1;
Fig. 7 is the hydrogen nuclear magnetic resonance spectrogram of the compound K of embodiment 1;
Fig. 8 is the carbon-13 nmr spectra figure of the compound K of embodiment 1;
Fig. 9 is the hydrogen nuclear magnetic resonance spectrogram of the compound L of embodiment 1;
Figure 10 is the carbon-13 nmr spectra figure of the compound L of embodiment 1;
Figure 11 is the hydrogen nuclear magnetic resonance spectrogram of the compound N of embodiment 1;
Figure 12 is the carbon-13 nmr spectra figure of the compound N of embodiment 1;
Figure 13 is the hydrogen nuclear magnetic resonance spectrogram of the compound P of embodiment 1;
Figure 14 is the carbon-13 nmr spectra figure of the compound P of embodiment 1;
Figure 15 is the hydrogen nuclear magnetic resonance spectrogram of the compd A of embodiment 1;
Figure 16 is the carbon-13 nmr spectra figure of the compd A of embodiment 1;
Figure 17 is the hydrogen nuclear magnetic resonance spectrogram of the compd B of embodiment 1;
Figure 18 is the carbon-13 nmr spectra figure of the compd B of embodiment 1;
Figure 19 is the hydrogen nuclear magnetic resonance spectrogram of the Compound C of embodiment 1;
Figure 20 is the carbon-13 nmr spectra figure of the Compound C of embodiment 1;
Figure 21 is the hydrogen nuclear magnetic resonance spectrogram of the Compound D of embodiment 1;
Figure 22 is the carbon-13 nmr spectra figure of the Compound D of embodiment 1;
Figure 23 is the hydrogen nuclear magnetic resonance spectrogram of the compd E of embodiment 1;
Figure 24 is the carbon-13 nmr spectra figure of the compd E of embodiment 1;
Figure 25 is the hydrogen nuclear magnetic resonance spectrogram of the compound F 17-hydroxy-corticosterone of embodiment 1;
Figure 26 is the carbon-13 nmr spectra figure of the compound F 17-hydroxy-corticosterone of embodiment 1;
Figure 27 is the hydrogen nuclear magnetic resonance spectrogram of the glossy ganoderma alcohol of embodiment 1;
Figure 28 is the carbon-13 nmr spectra figure of the glossy ganoderma alcohol of embodiment 1;
Figure 29 is the hydrogen nuclear magnetic resonance spectrogram of the glossy ganoderma alcohol of comparative example 1;
Figure 30 is the carbon-13 nmr spectra figure of the glossy ganoderma alcohol of comparative example 1.
Embodiment
For the ease of understanding the present invention, below with reference to relevant drawings, the present invention is described more fully.Preferred embodiment of the present invention is given in accompanying drawing.But the present invention can realize in many different forms, is not limited to embodiment described herein.On the contrary, provide the object of these embodiments be make the understanding of disclosure of the present invention more comprehensively thorough.
As shown in Figure 1, the preparation method of the glossy ganoderma alcohol of an embodiment, comprises the steps:
Step S110: at anhydrous condition, by structural formula is compd A mix in the first organic solvent with the first catalyzer, 85 DEG C of insulation reaction 20 hours under the atmosphere of carbon monoxide, obtaining structural formula is compd B.
Wherein, the anhydrous organic solvent that the first organic solvent can be commonly used for this area, such as, anhydrous 1,2-ethylene dichloride, anhydrous methylene chloride, chloroform, tetrahydrofuran (THF), benzene, toluene or acetone; Be preferably anhydrous 1,2-ethylene dichloride.
Wherein, the first catalyzer is rhodium catalyst, and such as, four carbonyl diurethane chlorination two rhodiums, chlorination cyclooctadiene base rhodium dipolymer, trans-bis-(triphenylphosphine) close rhodium carbonyl chloride or carbonyl triphenylphosphine rhodium chloride; Be preferably four carbonyl diurethane chlorination two rhodium [RhCl (CO) 2] 2.Wherein, the mass ratio of the first catalyzer and compd A is 108:13.
Concrete, after step silo, also comprise the purification step to compd B, be specially: the organic phase in the reaction solution obtain 85 DEG C of insulation reaction under the atmosphere of carbon monoxide after 20 hours is isolated, by organic phase concentrated by rotary evaporation, then through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:6 and the mixture of normal hexane), the compd B of purifying is obtained.
Refer to Fig. 2, wherein, compd A prepares by following steps, and concrete steps are:
Step S111: in 0 DEG C, by methyltriphenylphosphonium bromide (Ph 3pCH 3br), tertiary butyl potassium alcoholate and structural formula are compound G mix in the 6th organic solvent, obtain reaction system, reaction system be warming up to room temperature, and at room temperature react 2 hours, through cancellation reaction, obtaining structural formula is compound H.
Wherein, in step S111, heating-up time reaction system being warming up to room temperature is 10 minutes.
Wherein, the organic solvent that the 6th organic solvent can be commonly used for this area, is preferably tetrahydrofuran (THF) (THF).
Wherein, in 0 DEG C, by methyltriphenylphosphonium bromide (Ph 3pCH 3br) step that, tertiary butyl potassium alcoholate and compound G mix in the 6th organic solvent is specially: be dissolved in by methyltriphenylphosphonium bromide in the 6th organic solvent, at 0 DEG C, add tertiary butyl potassium alcoholate, and at 0 DEG C Keep agitation condition under add the organic solution of compound G.Wherein, the mol ratio of methyltriphenylphosphonium bromide and tertiary butyl potassium alcoholate is 1:1; The mol ratio of compound G and methyltriphenylphosphonium bromide is 97.04:116.5.
Wherein, the reagent that the cancellation reaction in step S111 uses is saturated aqueous ammonium chloride solution.
Wherein, in step S111, cancellation also comprises the step of extraction: by reacted for cancellation reactant extracted with diethyl ether after reacting, and uses salt solution to clean and use anhydrous sodium sulfate drying, then revolves to boil off to desolventize.
Step S112: be that 1:1:0.2 mixes in the 7th organic solvent according to mol ratio by compound H and acetic acid iodobenzene and tosic acid, then methyl alcohol is added at 0 DEG C, under room temperature, carry out ring expansion, obtaining structural formula is compound I.
Wherein, after step S112, also comprise the step of the separation and purification to Compound I: obtain concentrated solution by concentrated in a vacuum for the reactant after ring expansion, methylene dichloride and water that volume ratio is 1:1 is added in concentrated solution, then with salt washing, organic phase is merged, and dry organic phase, then by organic phase in column chromatography purification, obtain the Compound I of purifying.
Wherein, the 7th organic solvent is CH 3cN.
Step S113: by Compound I and formaldehyde, diethylamine hydrochloride (Et 2and diethylamine (Et NHHCl) 2nH) mix in the 8th organic solvent, and carry out methylenation in 105 DEG C, then through cancellation reaction, obtaining structural formula is compound J.Wherein, formaldehyde, diethylamine hydrochloride (Et 2and diethylamine (Et NHHCl) 2nH) mol ratio is 1:1:1.
Wherein, the 8th organic solvent is dioxan.
Wherein, the mol ratio of Compound I and formaldehyde is 165:34.08.
Wherein, in step S113, the reagent that cancellation reaction uses is saturated aqueous ammonium chloride solution.
In step S113, after cancellation reaction, also comprise the purification procedures to compound J: by reacted for cancellation reaction solution extracted with diethyl ether, merge organic phase and drying, obtain crude product, by crude product column chromatography purification (elutriant is volume ratio is the ether of 1:10 and the mixed solution of normal hexane), obtain the compound J of purifying.
Step S114: at-35 DEG C, by compound J, (R)-2-methyl-CBS-oxazaborolidine-oxazaborolidine and borine (BH 3) mix in the 9th organic solvent, and carry out asymmetric carbonyl reduction reaction in-35 DEG C, then through cancellation reaction, obtaining structural formula is compound K.
Wherein, the R in (R)-2-methyl-CBS-oxazaborolidine-oxazaborolidine represents that this compound is the chipal compounds of R configuration.
Wherein, compound J, (R)-2-methyl-CBS-oxazaborolidine and borine are mixed in the 9th organic solvent, and be specially in-35 DEG C of steps of carrying out asymmetric carbonyl reduction reaction: compound J is dissolved in the 9th organic solvent, be cooled to-35 DEG C, add (R)-2-methyl-CBS-oxazaborolidine under agitation condition, continue stirring 1 hour, then be cooled to-35 DEG C, add the organic solution of borine, stir and carry out asymmetric carbonyl reduction reaction.
Wherein, the 9th organic solvent is tetrahydrofuran (THF).
Wherein, in step S114, the reagent that cancellation reaction uses is saturated aqueous ammonium chloride solution.
In step S114, after cancellation reaction, also comprise the purification procedures to compound K: by reacted for cancellation reaction solution extracted with diethyl ether, merge organic phase and drying, obtain crude product, by crude product column chromatography purification (elutriant is volume ratio is the ether of 1:5 and the mixture of normal hexane), obtain the compound K of purifying.
Wherein, compound J is 17.67:1.78 with the mol ratio of (R)-2-methyl-CBS-oxazaborolidine; The mol ratio of compound J and borine is 1:2.
Step S115: at 0 DEG C, compound K is mixed in the tenth organic solvent with sodium hydrogen phosphate, metachloroperbenzoic acid (m-CPBA), and carry out oxidizing reaction in 0 DEG C, react through cancellation, obtain reactant, then at 0 DEG C, reactant is mixed with sodium bicarbonate and Dai Si Martin oxygenant (DMP), under room temperature, carry out oxidizing reaction, again through cancellation reaction, obtaining structural formula is compound L.
Wherein, at 0 DEG C, compound K is mixed in the tenth organic solvent with sodium hydrogen phosphate, metachloroperbenzoic acid, and be specially in 0 DEG C of step of carrying out oxidizing reaction: compound K is dissolved in the tenth organic solvent, sodium hydrogen phosphate and metachloroperbenzoic acid is added under the condition of ice-water bath, and in 0 DEG C of insulation reaction.
Wherein, the tenth organic solvent is benzene, toluene, methylene dichloride, acetonitrile or tetrahydrofuran (THF); Be preferably benzene.
Wherein, sodium hydrogen phosphate can pass through 12 hypophosphite monohydrate hydrogen sodium (Na 2hPO 4.12H 2o) mode adds.
Wherein, in step S115, mixed, and carry out oxidizing reaction in 0 DEG C by compound K with sodium hydrogen phosphate, metachloroperbenzoic acid in the tenth organic solvent, in the step of cancellation reaction, the reagent that cancellation reaction uses is Sulfothiorine saturated solution.
Wherein, the mol ratio of compound K and sodium hydrogen phosphate is 1:2, and the mol ratio of compound K and metachloroperbenzoic acid is 35.04:42.05.
Wherein, step S115 is specially: at 0 DEG C, by compound K and sodium hydrogen phosphate, metachloroperbenzoic acid (m-CPBA) mixes in the tenth organic solvent, and carry out oxidizing reaction in 0 DEG C, react through cancellation, obtain reactant, methylene dichloride is added in reactant, through washing, obtain organic phase, merge organic phase, crude product is obtained through concentrated, and crude product is dissolved in methylene dichloride, sodium bicarbonate and Dai Si Martin oxygenant (DMP) is added under the condition of ice-water bath, and carry out oxidizing reaction in stirred at ambient temperature, react through cancellation again, obtain compound L.
Wherein, mixed by reactant, under room temperature, carry out oxidizing reaction with sodium bicarbonate and Dai Si Martin oxygenant (DMP), in the step of cancellation reaction, the reagent that cancellation reaction uses is saturated hypo solution.
Wherein, in step S115, reactant is mixed with sodium bicarbonate and Dai Si Martin oxygenant (DMP), under room temperature, carries out oxidizing reaction, after the step of cancellation reaction, also comprise the step of compound L being carried out to separation and purification, be specially: with the reacted reactant of extracted with diethyl ether cancellation, obtain organic phase, organic phase merged dry, through column chromatography purification (elutriant is volume ratio is the normal hexane of 1:5 and the mixed solution of ethyl acetate), obtain the compound L of purifying.
Wherein, in step S115, sodium bicarbonate is 70.08:52.56 with the mol ratio wearing this Martin's oxygenant (DMP).Wherein, the mol ratio of sodium hydrogen phosphate and sodium bicarbonate is 1:1.
Step S116: in-78 DEG C, by compound L and two (trimethyl silicon based) Lithamide (LiHMDS) and ethyl cyanoformate (NCCOOCH 3) mix in the 11 organic solvent, and react 2 hours at-78 DEG C, then through cancellation reaction, obtaining structural formula is compound M.
Wherein, in step S116, the step that compound L and two (trimethyl silicon based) Lithamide and ethyl cyanoformate mix in the 11 organic solvent is specially: compound L is dissolved in the 11 organic solvent, be cooled to-78 DEG C, two (trimethyl silicon based) Lithamide is added under stirring, stirring reaction 45 minutes, adds compound ethyl cyanoformate.
Wherein, in step S116, the reagent that cancellation reaction uses is saturated aqueous ammonium chloride solution.
Concrete, in step S116, after cancellation reaction, also comprise the purification procedures to compound M: use the reacted reaction solution of extracted with diethyl ether cancellation, through washing, obtain organic phase, organic phase is merged and drying, through concentrated, then through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:10 and the mixed solution of normal hexane).
Wherein, compound L is 16.93:20.31 with the mol ratio of two (trimethyl silicon based) Lithamide; The mol ratio of two (trimethyl silicon based) Lithamide and ethyl cyanoformate is 1:1.
Wherein, the 11 organic solvent is tetrahydrofuran (THF) (THF).
Step S117: at-20 DEG C, by compound M and tetrabutyl ammonium fluoride (TBAF) and structural formula is compound R mix in the 12 organic solvent, and at-20 DEG C react 10 hours, through cancellation reaction, obtaining structural formula is compound N.
Concrete, in step S117, at-20 DEG C, compound M is specially with the step that tetrabutyl ammonium fluoride and compound R mix in the 12 organic solvent: compound M is dissolved in the 12 organic solvent, under the condition of-20 DEG C, add compound R, then add the organic solution of tetrabutyl ammonium fluoride.
Wherein, in step S117, the solvent that cancellation reaction uses is saturated aqueous ammonium chloride solution.
Concrete, in step S117, after cancellation reaction, also comprise the purification procedures to compound N: use ether (EtOAc) to extract the reacted reaction solution of cancellation, obtain organic phase, organic phase is merged and drying, through concentrated by rotary evaporation, then through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:2 and the mixed solution of normal hexane).
Wherein, the 12 organic solvent is tetrahydrofuran (THF), ether, benzene or toluene; Be preferably tetrahydrofuran (THF) (THF).
Wherein, in step S117, the mol ratio of tetrabutyl ammonium fluoride and compound R is 1:1; The mol ratio of tetrabutyl ammonium fluoride and compound L is 25.4:16.93.
Step S118: by compound N, sodium iodide (NaI) and trifluoroacetic acid (CF at 0 DEG C 3cO 2h) mix in the 13 organic solvent, and 0 DEG C of reaction 1 hour, be then warming up to room temperature reaction 3 hours, through cancellation reaction, obtaining structural formula is compound P.
Wherein, in step S118, the reagent that cancellation reaction uses is water.
Wherein, the 13 organic solvent is acetonitrile (CH 3cN).
Wherein, the mol ratio of compound N and sodium iodide is 1:10; The mol ratio of compound N and trifluoroacetic acid is 1:2.
Wherein, in step S118, after cancellation reaction, also comprise the purification procedures to compound P: use the reacted reaction solution of dichloromethane extraction cancellation, obtain organic phase, organic phase merged, wash through Sulfothiorine again, dry again, through concentrated by rotary evaporation, then through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:20 and the mixed solution of normal hexane).
Step S119: at 0 DEG C, by compound P and cerous compounds and sodium borohydride (NaBH 4) mix in the 14 organic solvent, and carry out reduction reaction in 0 DEG C, through cancellation reaction, obtain compd A.
Wherein, in step S119, at 0 DEG C, compound P is specially with the step that cerous compounds and sodium borohydride mix in the 14 organic solvent: compound P is dissolved in the 14 organic solvent, then at 0 DEG C, add cerous compounds, insulated and stirred 1 hour, then adds sodium borohydride.Wherein, the 14 organic solvent is ethanol.
Wherein, cerous compounds can be added by the mode of Cerous chloride heptahydrate.
Wherein, in step S119, the reagent that cancellation reaction uses is saturated aqueous ammonium chloride solution.
Wherein, in step S119, after cancellation reaction, also comprise the purification procedures to compd A: use the reacted reaction solution of dichloromethane extraction cancellation, obtain organic phase, organic phase is merged and drying, through concentrated by rotary evaporation, then through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:6 and the mixed solution of normal hexane).
Wherein, the mol ratio of compound P and cerous compounds is 1.94:2.13; The mol ratio of cerous compounds and sodium borohydride is 1:1.
Step S120: at 0 DEG C, by compd B and sodium borohydride (NaBH 4) be that 1:10 mixes in alcohol according to mol ratio,
And in 0 DEG C of reduction reaction 1 hour, then through cancellation reaction, obtaining structural formula is compound C.
Wherein, in step S120, the reagent that cancellation reaction uses is saturated aqueous ammonium chloride solution.
Wherein, in the step s 120, after cancellation reaction, also comprise the purification procedures to Compound C: make to be extracted with ethyl acetate the reacted reaction solution of cancellation, obtain organic phase, organic phase is merged and drying, through concentrated by rotary evaporation, again through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:10 and the mixed solution of normal hexane), obtain the Compound C of purifying.
Wherein, alcohol can be methyl alcohol, ethanol, propyl alcohol or the trimethyl carbinol; Be preferably methyl alcohol.
Step S130: be that 1:20 mixes in the second organic solvent with tin anhydride according to mol ratio by Compound C, and carry out allylic oxidation reaction in 110 DEG C, obtaining structural formula is compound D.
Wherein, in step S130, the second organic solvent is dioxan, tetrahydrofuran (THF), ether, benzene, toluene, acetone or chloroform; Be preferably dioxan.
Wherein, in step s 130, which, after cancellation reaction, also comprise the purification procedures to Compound D: use silicagel column to filter reacted for allylic oxidation reaction solution, and use the solid on ethyl acetate washing silicagel column, obtain organic phase, organic phase is merged and drying, through concentrated by rotary evaporation, then through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:4 and the mixed solution of normal hexane), obtain the Compound D of purifying.
Step S140: under the atmosphere of hydrogen, mixes Compound D with the second catalyzer, carries out catalytic hydrogenation under room temperature in the 3rd organic solvent, obtains structural formula and is compd E.
Wherein, in step S140, under the atmosphere of hydrogen, Compound D mixed in the 3rd organic solvent with the second catalyzer, the step of carrying out catalytic hydrogenation under room temperature is specially: Compound D be dissolved in the 3rd organic solvent, passes into nitrogen to remove oxygen, then described second catalyzer is at room temperature added, then stop passing into nitrogen, and pass into hydrogen, at room temperature catalytic hydrogenation 3 hours.Wherein, the mol ratio of Compound D and the second catalyzer is 10:1.
Wherein, in step S140, the second catalyzer can have the carbon of palladium, platinum or rhodium, calcium carbonate or silicate for load; Be preferably load and have the carbon of palladium (be expressed as Pd/C, wherein, the load quality percentage composition of palladium is 10%); 3rd organic solvent is methyl alcohol, ethanol, ethyl acetate, benzene or toluene; Be preferably methyl alcohol.
Wherein, in step S140, after cancellation reaction, also comprise the purification procedures to compd E: use silicagel column to filter the reaction solution after catalytic hydrogenation, and use the solid on ethyl acetate washing silicagel column, obtain organic phase, organic phase is merged and drying, through concentrated by rotary evaporation, then through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:3 and the mixed solution of normal hexane), obtain the compd E of purifying.
Step S150: be that 59:20:71 mixes in the 4th organic solvent according to mol ratio by compd E, benzoyl peroxide (BPO) and N-bromo-succinimide (NBS), Bian position oxidizing reaction is carried out in 80 DEG C, react through cancellation again, then oxygenant is added, and at room temperature react 24 hours, obtaining structural formula is compound F 17-hydroxy-corticosterone.
Wherein, in step S150, the 4th organic solvent can be anhydrous tetracol phenixin, benzene, toluene or acetone; Be preferably anhydrous tetracol phenixin; After the step that compd E, benzoyl peroxide and N-bromo-succinimide are mixed in the 4th organic solvent, before the oxidizing reaction of Bian position, be also included in the step adding water in mixed compd E, benzoyl peroxide and N-bromo-succinimide; The water added and the mass ratio of compd E are 1:100.
Wherein, in step S150, in the step preparing compound F 17-hydroxy-corticosterone, after cancellation reaction, also comprise and reacted for cancellation reaction solution is extracted with ethyl acetate, obtain organic phase, merge organic phase and drying, through concentrated by rotary evaporation, obtain the crude product be separated; Wherein, oxygenant is added in crude product.
Wherein, after the step s 150, also comprise the purification procedures to compound F 17-hydroxy-corticosterone: reaction solution reaction under room temperature obtained after 24 hours uses silicagel column to filter, and use the solid on ethyl acetate washing silicagel column, obtain organic phase, organic phase is merged and drying, through concentrated by rotary evaporation, again through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:1 and the mixed solution of normal hexane), obtain the compound F 17-hydroxy-corticosterone of purifying.
Wherein, in step S150, oxygenant is for wearing this Martin's oxygenant (DMP) or Manganse Dioxide.
Wherein, the step of the cancellation reaction of step S150 is specially: the reaction solution after the oxidizing reaction of Bian position is cooled to 0 DEG C, then uses saturated sodium sulfite solution cancellation.
Step S160: at anhydrous condition, be that 21:665:280 in five organic solvent in mix by compound F 17-hydroxy-corticosterone and tert-butyl mercaptan (t-BuSH) and aluminum chloride according to mol ratio in 0 DEG C, again in 40 DEG C of insulation reaction after 12 hours, through cancellation reaction, obtaining structural formula is glossy ganoderma alcohol.
Wherein, in step S160, the step of cancellation reaction is specially: the reaction solution after insulation reaction is cooled to 0 DEG C, then uses frozen water cancellation, then adds saturated sodium dihydrogen phosphate.
In step S160, after cancellation reaction, also comprise the purification procedures to glossy ganoderma alcohol: make to be extracted with ethyl acetate the reacted reaction solution of cancellation, obtain organic phase, organic phase is merged and drying, through concentrated by rotary evaporation, then through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:2 and the mixed solution of normal hexane), obtain the glossy ganoderma alcohol of purifying.
Wherein, the 5th organic solvent is methylene dichloride.
The nmr spectrum of the glossy ganoderma alcohol that above-mentioned preparation method prepares conforms to the nmr spectrum of natural glossy ganoderma alcohol, thus natural glossy ganoderma alcohol can be replaced to use, to make up the deficiency of natural glossy ganoderma alcohol, thus meet the demand of people to glossy ganoderma alcohol, and above-mentioned preparation method is simple.
It is below specific embodiment part, wherein, hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of following compound are all obtained by the method for nucleus magnetic resonance, instrument and the test condition of test use are as follows: Br ü ker Advance 300 (1H:300MHz, 13C:75.5MHz), Br ü ker Advance 500 (1H:500MHz, 13C:125MHz), uses non-deuterated solvent residual in TMS or deuterated solvent to do interior mark:
Embodiment 1
The preparation method of the preparation method of the glossy ganoderma alcohol of the present embodiment is as follows:
(1) compound G (20.00g, 97.04mmol) is dissolved in 50mL tetrahydrofuran (THF), obtains the tetrahydrofuran solution of compound G; By methyltriphenylphosphonium bromide (Ph 3pCH 3br) (41.36g, 116.5mmol) is dissolved in tetrahydrofuran (THF) (400mL) and obtains methyltriphenylphosphonium bromide (Ph 3pCH 3br) tetrahydrofuran solution, under the condition of 0 DEG C, tertiary butyl potassium alcoholate (13.05g is added in the tetrahydrofuran solution of methyltriphenylphosphonium bromide, 116.5mmol), and at 0 DEG C Keep agitation condition under, join in the tetrahydrofuran solution of methyltriphenylphosphonium bromide by the tetrahydrofuran solution of compound G, churning time is 45 minutes.Then reaction system was warming up to room temperature in 10 minutes, stirs 2 hours, add the saturated aqueous ammonium chloride solution of 100ml and carry out cancellation reaction; Then obtain the reacted product of cancellation, each 100mL with ether 3 extractions, cleaned by product salt solution, then use anhydrous sodium sulfate drying, filtrate is revolved steaming and is removed solvent, obtains the crude product (19.60g, 98%) containing compound H.The chemical equation of compound H is as follows:
(2) acetic acid iodobenzene (37.28g, 95.10mmol) is dissolved in CH 3in CN, obtain the organic solution that concentration is the acetic acid iodobenzene of 0.2mol/L, under the condition of magnetic agitation, crude product (the 19.60g of instillation containing compound H, 95.10mmol), and methyl alcohol and the tosic acid (3.28g of 2L is added at 0 DEG C, 19.2mmol), then react in stirred at ambient temperature and carry out ring expansion in 3 hours, by the reactant concentrated concentrated solution obtaining oily in a vacuum, 150mL methylene dichloride and 150mL water is added in concentrated solution, then wash with salt, obtain organic phase, merge organic phase and drying, again through column chromatography purification (elutriant is: volume is the ethyl acetate of 1:100 and the mixed solution of normal hexane), obtain yellow viscous liquid 19.89g, i.e. Compound I, productive rate 95%, the chemical equation of Compound I is:
Wherein, Fig. 3 and Fig. 4 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the Compound I that the present embodiment prepares.
(3) Compound I (16.9ml, 165mmol) is dissolved in dioxan (100mL), adds formaldehyde (aq.2.77g, 34.08mmol), diethylamine hydrochloride (Et at normal temperatures 2nHHCl) (3.73g, 34.08mmol) and diethylamine (Et 2nH) (2.49g, 34.08mmol), is heated to 105 DEG C, stirs and carries out methylenation in 45 minutes, then adds saturated ammonium chloride solution (50mL) and carries out cancellation reaction; The reacted reaction solution of extracted with diethyl ether cancellation of 100mL is used through 3 times, merge organic phase, and it is dry, obtain crude product, by crude product column chromatography purification (elutriant is: volume ratio is the ether of 1:10 and the mixed solution of normal hexane), obtain colourless oil liquid 5.17g, i.e. compound J, overall yield 98%.The chemical equation of compound J is:
Wherein, Fig. 5 and Fig. 6 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the compound J that the present embodiment prepares.
(4) by compound J (4.1g, 17.67mmol) be dissolved in tetrahydrofuran (THF) (100mL), be cooled to-35 DEG C, (R)-2-methyl-CBS-oxazaborolidine (1.78mmol is added under stirring, 1.78ml), continue stirring 1 hour, then be cooled to-35 DEG C, then instill the borine (BH that 35.34ml concentration is 1mol/L 3) tetrahydrofuran solution, continue stirring within 3 hours, carry out asymmetric carbonyl reduction reaction.Use 50mL saturated ammonium chloride solution cancellation reaction, and use the reacted reaction solution of extracted with diethyl ether cancellation 3 times, each 100mL, merge organic phase and drying, after concentrated by rotary evaporation, through column chromatography purification (elutriant is: volume ratio is the ether of 1:5 and the mixed solution of normal hexane), obtain yellow oily liquid 3.76g, i.e. compound K, productive rate 91%.[α] D＝4.8(c＝0.53,MeOH)。The chemical equation of compound K is:
Wherein, Fig. 7 and Fig. 8 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the compound K that the present embodiment prepares.
(5) compound K (8.20g, 35.04mmol) is dissolved in 200mL benzene (benzene), under ice bath, adds Na 2hPO 4.12H 2o (35.1g, 70.08mmol), then metachloroperbenzoic acid (m-CPBA) (7.27g is added, 42.05mmol), 0 DEG C of oxidizing reaction 4 hours, adds the cancellation of Sulfothiorine (50mL) saturated solution, 300mL methylene dichloride is added in the reacted reactant of cancellation, through 30mL washing, the organic phase obtained is merged concentrated, obtains crude product.Gained crude product is dissolved in methylene dichloride (DCM) (100mL), under ice bath, adds NaHCO 3(5.89g, 70.08mmol) and wear this Martin's oxygenant (DMP) (22.32g, 52.56mmol), stirred at ambient temperature oxidizing reaction 1.5 hours, then 50mL saturated sodium thiosulfate solution cancellation reaction is added, use the reacted reactant of diethyl ether solution extraction cancellation of 3 100ml, the organic phase obtained is merged dry, through column chromatography purification (elutriant is: volume ratio is the normal hexane of 1:5 and the mixed solution of ethyl acetate), obtain compound L 7.04g altogether, productive rate 81%; [α] d=-135.7 (c=1.00, MeOH).The chemical equation of compound L is:
Wherein, Fig. 9 and Figure 10 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the compound L that the present embodiment prepares.
(6) by compound L (4.20g, 16.93mmol) be dissolved in tetrahydrofuran (THF) (THF) (100mL), be cooled to-78 DEG C, add in the tetrahydrofuran solution of two (trimethyl silicon based) Lithamides (LiHMDS) of the 1mol/L of 20.31mL under stirring, stir 45 minutes, then add ethyl cyanoformate (NCCOOCH 3) (1.73g, 20.31mmol), 2h is stirred under-78 DEG C of conditions, then the ammonium chloride solution cancellation that 50ml is saturated is added, use for 3 times 100mL ether to extract the reacted reactant of cancellation, through washing, merge organic being harmonious also and drying, through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:10 and the mixed solution of normal hexane) after concentrated, obtain compound M.The chemical equation of compound M is:
(7) the compound M of preparation in step (6) is all dissolved in tetrahydrofuran (THF) (100ml), compound R (8.74g is added under-20 DEG C of conditions, 25.40mmol), then add the tetrahydrofuran solution of the tetrabutyl ammonium fluoride (TBAF) that 25.4mL concentration is 1mol/L in 20 DEG C, and under-20 DEG C of conditions, continue stirring reaction 10 hours.50mL saturated ammonium chloride solution is used to carry out cancellation reaction, 100mL ether is used for 3 times to extract the reacted reactant of cancellation, merge organic phase and drying, after concentrated by rotary evaporation, through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:2 and the mixture of normal hexane), obtain colorless solid compounds 3.50g, i.e. compound N, productive rate 62%.[α] D＝-101.7(c＝0.30,CH 3OH)。The chemical equation of compound N is:
Wherein, Figure 11 and Figure 12 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the compound N that the present embodiment prepares.
(8) compound N (1.00g, 3.03mmol) is dissolved in acetonitrile (100ml), under 0 DEG C of condition, adds sodium iodide (NaI) (4.54g, 30.30mmol) and trifluoroacetic acid (CF 3cO 2h) (0.48mL, 6.06mmol).This reaction system stirs 1h under 0 DEG C of condition, is then warming up to room temperature and continues to stir 3h.Use 50mL water to carry out cancellation reaction, use for 3 times the methylene dichloride of 100mL to extract the reacted reactant of cancellation, merge organic phase, then use saturated Na 2s 2o 3solution washing 3 times, each 30mL, drying, after concentrated by rotary evaporation, through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:20 and the mixed solution of normal hexane), obtains compound 874mg, i.e. compound P, productive rate 92%.[α] D＝-25.8(c＝0.58,MeOH)。The chemical equation of compound P is:
Wherein, Figure 13 and Figure 14 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the compound P that the present embodiment prepares.
(9) compound P (610mg, 1.94mmol) is dissolved in ethanol (20ml), then under 0 DEG C of condition, adds CeCl 3.7H 2o (612mg, 2.13mmol), continues this reaction system at 0 DEG C to stir 1h.Then, under 0 DEG C of condition, in this system, NaBH is added 4(81mg, 2.13mmol), and this reaction system is continued at 0 DEG C stir 5h carry out reduction reaction.Then saturated aqueous ammonium chloride (20mL) is used to carry out cancellation reaction, the reactant using dichloromethane extraction cancellation to react 3 times, each 20mL, merge organic phase and drying, through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:6 and the mixed solution of normal hexane) after concentrated by rotary evaporation, obtain compd A (386mg), productive rate 63%.[α] D＝-6.9(c＝0.25,MeOH)。The chemical equation of compd A is:
Wherein, Figure 15 and Figure 16 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the compd A that the present embodiment prepares.
(10) compd A (108mg, 0.34mmol) is dissolved in anhydrous 1,2-ethylene dichloride (20mL), then adds 13mg [RhCl (CO) 2] 2this reaction system is under the protection of carbon monoxide; in 85 DEG C of continuously stirring 20 hours; isolate organic phase; by organic phase concentrated by rotary evaporation; then in column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:6 and the mixture of normal hexane), compd B (92mg) is obtained, productive rate 86%.[α] D＝-201.1(c＝0.25,MeOH)。The chemical equation of compd B is:
Wherein, Figure 17 and Figure 18 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the compd B that the present embodiment prepares.
(11) compd B (53mg, 0.185mmol) is dissolved in methyl alcohol (CH 3oH) (10ml), then adds NaBH under 0 DEG C of condition 4(74mg, 1.85mmol), and 0 DEG C is stirred reduction reaction 1 hour.Use the aqueous solution (10mL) the cancellation reaction of saturated ammonium chloride, make to be extracted with ethyl acetate the reactant 3 times of cancellation reaction, each 10mL, merge organic phase and drying, through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:10 and the mixed solution of normal hexane) after concentrated by rotary evaporation, obtain Compound C (42mg), productive rate 89%.The chemical equation of Compound C is:
Wherein, Figure 19 and Figure 20 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the Compound C that the present embodiment prepares.
(12) Compound C (26mg, 0.091mmol) is dissolved in dioxan (10ml), adds compound S eO at ambient temperature 2(204mg, 1.82mmol), then this reaction system is warming up to 110 DEG C, and within 36 hours, carry out allylic oxidation reaction in 110 DEG C of stirrings, then reaction system is cooled to room temperature, reaction solution uses silicagel column to filter, and use the solid on ethyl acetate washing silicagel column, obtain organic phase, organic phase is merged and drying, through concentrated by rotary evaporation, then through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:4 and the mixed solution of normal hexane), obtain the Compound D (18mg) of purifying, productive rate 65%.The chemical equation of Compound D is:
Wherein, Figure 21 and Figure 22 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the Compound D that the present embodiment prepares.
(13) by Compound D (36mg, 0.12mmol) be dissolved in methyl alcohol (10mL), after use nitrogen removes the oxygen in this solution system, add catalyst P d/C (mass percentage of Pd is 10%) (12mg, 0.012mmol) at ambient temperature.Then nitrogen ball is replaced with hydrogen, and repeatedly after replacing hydrogen 6 times, at ambient temperature, this reaction system continuously stirring 3h under the atmosphere of hydrogen is carried out catalytic hydrogenation.Silicagel column is used to filter the reaction solution after catalytic hydrogenation, and use the solid on ethyl acetate washing silicagel column, obtain organic phase, organic phase is merged and drying, through concentrated by rotary evaporation, again through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:3 and the mixed solution of normal hexane), obtain the compd E (34mg) of purifying, productive rate 95%.The chemical equation of compd E is:
Wherein, Figure 23 and Figure 24 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the compd E that the present embodiment prepares.
(14) compd E (18mg, 0.059mmol) is dissolved in anhydrous CCl 4(6ml), add benzoyl peroxide (BPO) (4.8mg, 0.02mmol) and NBS (12.6mg, 0.071mmol) at ambient temperature, in this reaction system, then add the water of 0.18mg.This reaction system continuously stirring 2.5h under 80 DEG C of conditions is carried out Bian position oxidizing reaction, then reaction system is cooled to 0 DEG C, use the saturated NaHSO of 3mL 3solution cancellation is reacted, and makes to be extracted with ethyl acetate the reactant 6 times of cancellation reaction, each 10mL, merges organic phase and dry, obtains product after concentrated by rotary evaporation.
(15) product that step (14) obtains all is dissolved in anhydrous methylene chloride, add at ambient temperature and wear this Martin's oxygenant (DMP) (50mg, 0.118mmol), and at room temperature continuously stirring reaction 24h, silicagel column is used to filter to reaction solution, and use the solid on ethyl acetate washing silicagel column, obtain organic phase, organic phase is merged and drying, through concentrated by rotary evaporation, again through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:1 and the mixed solution of normal hexane), obtain the compound F 17-hydroxy-corticosterone (13mg) of purifying, productive rate 71%.The chemical equation of compound F 17-hydroxy-corticosterone is:
Wherein, Figure 25 and Figure 26 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the compound F 17-hydroxy-corticosterone that the present embodiment prepares.
(16) compound F 17-hydroxy-corticosterone (13mg, 0.042mmol) is dissolved in anhydrous methylene dichloride (3mL), under 0 DEG C of condition, adds tert-butyl mercaptan (t-BuSH) (1.5mL, 13.3mmol) and AlCl 3(75mg, 0.56mmol), is then slowly heated to 40 DEG C by this reaction system, and in 40 DEG C of continuously stirring reaction 12h, then this reaction system is cooled to 0 DEG C, slowly dropwise add frozen water (2mL) and carry out cancellation reaction, then add saturated NaH 2pO 4solution (3mL), and continue to stir 15min.Make to be extracted with ethyl acetate the reactant 6 times of cancellation reaction, each 10mL, merge organic phase and drying, through column chromatography purification (elutriant is: volume ratio is the ethyl acetate of 1:2 and the mixed solution of normal hexane) after concentrated by rotary evaporation, obtain glossy ganoderma alcohol (-)-Lingzhiol (5.8mg) of purifying, productive rate 71%.[α] D＝-89.7(c＝0.29，MeOH)。Wherein, the chemical equation of glossy ganoderma alcohol is:
Wherein, Figure 27 and Figure 28 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the glossy ganoderma alcohol that the present embodiment prepares.
Comparative example 1
The glossy ganoderma alcohol of comparative example 1 is the glossy ganoderma alcohol extracted from glossy ganoderma, namely natural glossy ganoderma alcohol.
Figure 29 and Figure 30 is respectively hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of the glossy ganoderma alcohol of comparative example 1, can show that from figure glossy ganoderma alcohol prepared by embodiment 1 conforms to the chemical structure of the glossy ganoderma alcohol of comparative example 1, namely the glossy ganoderma alcohol that prepared by embodiment 1 is identical with the glossy ganoderma alcohol of natural extract, the glossy ganoderma alcohol of natural plant extract can be replaced, to make up the glossy ganoderma alcohol of extracted form natural plant.
Embodiment 2
Being prepared as follows of the glossy ganoderma alcohol of the present embodiment:
Preparation process (1) ~ (14) are roughly the same with embodiment 1, difference is only that will wear this Martin's oxygenant (DMP) in step (15) replaces with Manganse Dioxide, and step (16) is also roughly the same with embodiment 1.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Claims (10)

1. a preparation method for glossy ganoderma alcohol, is characterized in that, comprises the steps:
At anhydrous condition, by structural formula be compd A mix in the first organic solvent with the first catalyzer, 85 DEG C of insulation reaction 20 hours under the atmosphere of carbon monoxide, obtaining structural formula is compd B;
At 0 DEG C, be that 1:10 in alcohol in mix with sodium borohydride according to mol ratio by described compd B, and in 0 DEG C of reduction reaction 1 hour, then through cancellation reaction, obtaining structural formula is compound C;
Be that 1:20 in second organic solvent in mix with tin anhydride according to mol ratio by described Compound C, and carry out allylic oxidation reaction in 110 DEG C, obtaining structural formula is compound D;
Under the atmosphere of hydrogen, described Compound D mixed in the 3rd organic solvent with the second catalyzer, carry out catalytic hydrogenation under room temperature, obtaining structural formula is compd E;
Be that 59:20:71 mixes in the 4th organic solvent by described compd E, benzoyl peroxide and N-bromo-succinimide according to mol ratio, carry out Bian position oxidizing reaction in 80 DEG C, then through cancellation reaction, then add oxygenant, and at room temperature react 24 hours, obtaining structural formula is compound F 17-hydroxy-corticosterone; And
In anhydrous conditions, be that 21:665:280 in five organic solvent in mix by described compound F 17-hydroxy-corticosterone and tert-butyl mercaptan and aluminum chloride according to mol ratio in 0 DEG C, then in 40 DEG C of insulation reaction after 12 hours, through cancellation reaction, obtaining structural formula is glossy ganoderma alcohol.
2. the preparation method of glossy ganoderma alcohol according to claim 1, is characterized in that, described first catalyzer is four carbonyl diurethane chlorination two rhodiums; Described first organic solvent is anhydrous 1,2-ethylene dichloride.
3. the preparation method of glossy ganoderma alcohol according to claim 1, is characterized in that, described alcohol is methyl alcohol.
4. the preparation method of glossy ganoderma alcohol according to claim 1, is characterized in that, described second organic solvent is dioxan.
5. the preparation method of glossy ganoderma alcohol according to claim 1, is characterized in that, described second catalyzer is the carbon that load has palladium; The mol ratio of described second catalyzer and described Compound D is 1:10; Described 3rd organic solvent is methyl alcohol.
6. the preparation method of glossy ganoderma alcohol according to claim 1, it is characterized in that, described under the atmosphere of hydrogen, described Compound D is mixed in described 3rd organic solvent with described second catalyzer, described catalytic hydrogenation is carried out under room temperature, the step obtaining described compd E is specially: described Compound D be dissolved in described 3rd organic solvent, pass into nitrogen to remove oxygen, then described second catalyzer is at room temperature added, then stop passing into nitrogen, and pass into hydrogen, at room temperature react 3 hours.
7. the preparation method of glossy ganoderma alcohol according to claim 1, is characterized in that, described 4th organic solvent is anhydrous tetracol phenixin; After the step that described compd E, benzoyl peroxide and N-bromo-succinimide are mixed in described 4th organic solvent, before the oxidizing reaction of described Bian position, be also included in the step adding water in mixed described compd E, benzoyl peroxide and N-bromo-succinimide; The described water added and the mass ratio of described compd E are 1:100; Described oxygenant is for wearing this Martin's oxygenant or Manganse Dioxide.
8. the preparation method of glossy ganoderma alcohol according to claim 1, is characterized in that, described 5th organic solvent is methylene dichloride.
9. the preparation method of glossy ganoderma alcohol according to claim 1, it is characterized in that, in the step of the described compound F 17-hydroxy-corticosterone of preparation, after described cancellation reaction, also comprise the step being carried out by reacted for described cancellation reactant being separated, be specially: reacted for described cancellation reaction solution is extracted with ethyl acetate, obtain organic phase, merge organic phase and drying, through concentrated by rotary evaporation, obtain the crude product be separated; Wherein, described oxygenant is added in described crude product.
10. the preparation method of glossy ganoderma alcohol according to claim 1, is characterized in that, also comprises the preparation process of described compd A, is specially:
In 0 DEG C, by methyltriphenylphosphonium bromide, tertiary butyl potassium alcoholate and structural formula be compound G mix in the 6th organic solvent, obtain reaction system, described reaction system be warming up to room temperature, and at room temperature react 2 hours, through cancellation reaction, obtaining structural formula is compound H;
Be that 1:1:0.2 mixes in the 7th organic solvent by described compound H, acetic acid iodobenzene and tosic acid according to mol ratio, then add methyl alcohol at 0 DEG C, under room temperature, carry out ring expansion, obtaining structural formula is compound I;
Described Compound I is mixed with formaldehyde, diethylamine hydrochloride and diethylamine in the 8th organic solvent, and carries out methylenation in 105 DEG C, then through cancellation reaction, obtaining structural formula is compound J, wherein, the mol ratio of described formaldehyde, diethylamine hydrochloride and diethylamine is 1:1:1;
At-35 DEG C, described compound J, (R)-2-methyl-CBS-oxazaborolidine-oxazaborolidine and borine are mixed in the 9th organic solvent, and carries out asymmetric carbonyl reduction reaction in-35 DEG C, then through cancellation reaction, obtaining structural formula is compound K;
At 0 DEG C, described compound K is mixed in the tenth organic solvent with sodium hydrogen phosphate, metachloroperbenzoic acid, and carry out oxidizing reaction in 0 DEG C, react through cancellation, obtain reactant, then at 0 DEG C, described reactant is mixed with sodium bicarbonate and Dai Si Martin oxygenant, and carry out oxidizing reaction under room temperature, through cancellation reaction, obtaining structural formula is compound L;
In-78 DEG C, described compound L is mixed with two (trimethyl silicon based) Lithamide and ethyl cyanoformate in the 11 organic solvent, and reacts 2 hours at-78 DEG C, then through cancellation reaction, obtaining structural formula is compound M;
At-20 DEG C, by described compound M and tetrabutyl ammonium fluoride and structural formula be compound R mix in the 12 organic solvent, and at-20 DEG C react 10 hours, through cancellation reaction, obtaining structural formula is compound N;
Described compound N, sodium iodide and trifluoroacetic acid are mixed in the 13 organic solvent at 0 DEG C, and 0 DEG C of reaction 1 hour, be then warming up to room temperature reaction 3 hours, through cancellation reaction, obtaining structural formula is compound P; And
At 0 DEG C, described compound P is mixed with cerous compounds and sodium borohydride in the 14 organic solvent, and carries out reduction reaction in 0 DEG C, through cancellation reaction, obtain described compd A.
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CN105111267A (en) * 2015-10-09 2015-12-02 上海市农业科学院 Preparation method of ganoderol B
CN106117177A (en) * 2016-04-26 2016-11-16 中国科学院昆明植物研究所 Optical activity Ganoderma phenol intermediate and preparation method thereof
CN115010622A (en) * 2022-06-20 2022-09-06 山东百启生物医药有限公司 Preparation method of 2-bromo-5-cyanobenzaldehyde

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CN103435580A (en) * 2013-09-24 2013-12-11 中国科学院昆明植物研究所 Lingzhiol A and application of lingzhiol A in drug production and foods

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CN103435580A (en) * 2013-09-24 2013-12-11 中国科学院昆明植物研究所 Lingzhiol A and application of lingzhiol A in drug production and foods

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105111267A (en) * 2015-10-09 2015-12-02 上海市农业科学院 Preparation method of ganoderol B
CN106117177A (en) * 2016-04-26 2016-11-16 中国科学院昆明植物研究所 Optical activity Ganoderma phenol intermediate and preparation method thereof
CN115010622A (en) * 2022-06-20 2022-09-06 山东百启生物医药有限公司 Preparation method of 2-bromo-5-cyanobenzaldehyde
CN115010622B (en) * 2022-06-20 2024-01-09 山东百启生物医药有限公司 Preparation method of 2-bromo-5-cyanobenzaldehyde

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