CN103483349B

CN103483349B - Synthesis method for Cladiellin natural products Pachycladin D with important biological activity

Info

Publication number: CN103483349B
Application number: CN201310400640.7A
Authority: CN
Inventors: 岳国宗; 张云; 李闯创; 罗佗平; 杨震
Original assignee: Peking University Shenzhen Graduate School
Current assignee: Peking University Shenzhen Graduate School
Priority date: 2013-09-05
Filing date: 2013-09-05
Publication date: 2015-05-13
Anticipated expiration: 2033-09-05
Also published as: CN103483349A

Abstract

The invention discloses a synthesis method for natural products Pachycladin D, wherein the structural formula of the natural products Pachycladin D is defined in the specification, isopropyl is introduced by myers chiral auxiliary to generate a compound L, a catalytic reaction is performed on 1,3-bis(2,6-di-isopropylphenyl) imidazole-2-idene gold (I) chloride and silver hexafluoroantimonate, a [6,5] parallel-ring system is constructed in one step to generate a compound F and a compound Fa efficiently and simply, then an olefin metathesis reaction is catalyzed by virtue of a catalyst Zhan 1B, so as to obtain a compound C with a high yield, and the natural products Pachycladin D are obtained from the compound C by virtue of a few of simple functional conversion steps. The synthesis method is simple in reaction operation, high in the yield of each step, and capable of being widely popularized and applied.

Description

There is the synthetic method of the Cladiellin class natural product Pachycladin D of important biomolecule activity

Technical field

The present invention relates to the field of chemical synthesis, particularly relate to the synthetic method of Cladiellin class natural product Pachycladin D.

Background technology

Cladiellin compounds is separated to obtain the compound that a class has structure diversity from marine invertebrates (as gorgonian, alcynorian etc.).A lot of natural product is had to have significant biological activity in this family, pharmaceutical use is high, such as Sclerophytin A is in the news and has significant cytotoxicity to the lymphoblastic leukemia cell lines (L1210) of mouse, and IC50 value reaches 3nM, has potential anti-tumor capacity.Vigulariol in vitro cytotoxicity shows to have the activity of anti-Lu-csf-1 (A-549) in testing.Polyanthellin A, can suppress plasmodium falciparum, and IC50 value reaches 44 μMs.Experimental data shows that Pachycladin D has the activity that anti-human prostate cancer cell invasion is active and suppress Human Prostate Cancer Cells to be moved, and is a kind of potential lead compound, and this is that the new medicine of exploitation provides good basis.

These compounds and analogue as the lead compound of Small-molecule probe or new drug development, can be of great significance development and design new drug tool.But because the natural content of this compounds is rare, limit its systematic study and extensively use.

Summary of the invention

Based on this, be necessary the problem for Cladiellin class natural product Pachycladin D natural content rareness, the synthetic method of a kind of Cladiellin class natural product Pachycladin D is provided.

A synthetic method of natural product Pachycladin D, comprises the following steps:

Compd B is dissolved in methylene dichloride, TSIM is added under room temperature, the mol ratio of described compd B and described TSIM is 1:10, stir 1 hour, add saturated ammonium chloride solution cancellation reaction, obtain the first reaction solution, described first reaction solution separation and purification is obtained compound B-11, and the structural formula of described compd B and described compound B-11 is as follows:

Compd B: compound B-11:

Described compound B-11 is dissolved in toluene, add burgess reagent, 70 DEG C are stirred 20 minutes, are cooled to 0 DEG C, add the tetrahydrofuran solution that concentration is the tetrabutyl ammonium fluoride of 1.0mol/L, the mol ratio of described compound B-11, burgess reagent and tetrabutyl ammonium fluoride is 0.105:0.4:0.076, stir 15 minutes, add saturated ammonium chloride solution cancellation reaction, obtain the second reaction solution, described second reaction solution separation and purification is obtained compd A, and the structural formula of described compd A is as follows:

Compd A:

Described compd A is dissolved in toluene, add the tetrahydrofuran solution that concentration is the methylmagnesium-chloride of 3.0mol/L, the mol ratio of described compd A and described methylmagnesium-chloride is 1:90, be heated to 100 DEG C, stir 30 minutes, be cooled to 0 DEG C, add saturated ammonium chloride solution cancellation reaction, obtain the 3rd reaction solution, described 3rd reaction solution separation and purification is obtained Compound C ladillisin, and the structural formula of described Compound C ladillisin is as follows:

Compound C ladillisin:

Described Compound C ladillisin is dissolved in methylene dichloride, Manganse Dioxide is added under room temperature, the mol ratio of described Compound C ladillisin and described Manganse Dioxide is 1:60, stir 2 hours, obtain the 4th reaction solution, described 4th reaction solution separation and purification is obtained natural product Pachycladin D, and the structural formula of described natural product Pachycladin D is as follows:

Natural product Pachycladin D:

Wherein in an embodiment, described first reaction solution separation and purification is obtained in the step of compound B-11, the method of described separation and purification is specially: be extracted with ethyl acetate by described first reaction solution, get organic phase anhydrous sodium sulfate drying, after filtering, removing methylene dichloride obtains oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:6 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compound B-11.

Wherein in an embodiment, described 3rd reaction solution separation and purification is obtained in the step of Compound C ladillisin, the method of described separation and purification is specially: be extracted with ethyl acetate by institute the 3rd reaction solution, get organic phase anhydrous sodium sulfate drying, after filtering, removing toluene and ethyl acetate obtain oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:6 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described Compound C ladillisin.

Wherein in an embodiment, described compd B is prepared by following steps:

Compound C is dissolved in chloroform, be cooled to-12 DEG C, add the chloroformic solution that mass percentage is the metachloroperbenzoic acid of 75%, the mol ratio of described Compound C and described metachloroperbenzoic acid is 1:1.4, stir 22 hours at-12 DEG C, add saturated sodium bicarbonate solution cancellation and be obtained by reacting the first mixed solution, described first mixed solution separation and purification is obtained Compound C 1 and Compound C 2, and the structural formula of described Compound C, Compound C 1 and Compound C 2 is as follows:

Compound C: compound C 1:

Compound C 2:

Described Compound C 1 and Compound C 2 mixing are dissolved in 1, in 4-dioxane, add the lithium hydroxide aqueous solution that concentration is 1.0mol/L, stir 1 hour, adding concentration is that the aqueous potassium hydrogen sulfate of 1.0mol/L stirs 15 minutes, add the acetonitrile solution that concentration is the trifluoromethayl sulfonic acid scandium of 0.04mol/L again, described Compound C 1, Compound C 2, , lithium hydroxide, the mol ratio of sal enixum and trifluoromethayl sulfonic acid scandium is 0.083:0.167:4.5:4.5:0.36, stir 6 hours, add saturated sodium bicarbonate solution cancellation and be obtained by reacting the second mixed solution, described second mixed solution separation and purification is obtained compd B, the structural formula of described compd B is as follows:

Compd B:

Wherein in an embodiment, described first mixed solution separation and purification is obtained in the step of Compound C 1 and Compound C 2, the method of described separation and purification is specially: by described first mixed solution chloroform extraction, get organic phase anhydrous magnesium sulfate drying, after filtering, removing chloroform obtains oily crude product, take volume ratio as the ethyl acetate of 1:10 ~ 1:20 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described Compound C 1 and Compound C 2.

Wherein in an embodiment, described Compound C is prepared by following steps:

Compound D is dissolved in toluene, be heated to reflux state, add Zhan 1B, the mol ratio of described Compound D and described Zhan 1B is 1:0.01 ~ 1:0.3, stir 8 hours, obtain reaction solution, described reaction solution separation and purification is obtained Compound C, the structural formula of described Compound D, Zhan 1B and Compound C is as follows:

Compound D: zhan 1B:

Compound C:

Wherein in an embodiment, described Compound D is prepared by following steps:

Under room temperature, 5-hexynoic acid is dissolved in N, in dinethylformamide, add the N that mol ratio is 3:1.1:1.1:1.1, N-diisopropylethylamine, I-hydroxybenzotriazole one water thing, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and (1S, 2S)-pseudoephenamine, described 5-hexynoic acid and described (1S, 2S) mol ratio of-pseudoephenamine is 1:1.1, stir 12 hours, the cancellation that adds water is reacted, and obtains compound M, the structural formula of described (1S, 2S)-pseudoephenamine and compound M is as follows:

(1S, 2S)-pseudoephenamine: compound M:

Described compound M is dissolved in tetrahydrofuran (THF), add lithium chloride, be cooled to-78 DEG C, add lithium diisopropylamine, stir 1 hour, rise to stirring at room temperature half an hour, be cooled to-78 DEG C again, add isopropyl iodide, the mol ratio of described compound M, lithium chloride, lithium diisopropylamine and isopropyl iodide is 1:6:4:6, rise to room temperature, stir 10 ~ 12 hours, add saturated ammonium chloride solution cancellation reaction, obtain the first solution, described first solution separating purifying is obtained compound L, and the structural formula of described compound L is as follows:

Compound L:

Described compound L being dissolved in volume ratio is in the trimethyl carbinol of 1:3 and the mixing solutions of water, add the TBAH aqueous solution that mass percentage is 40%, the mol ratio of described compound L and described TBAH is 1:5, be heated to reflux state, react 36 hours, be cooled to room temperature, adjust pH≤1, obtain the second solution, described second solution separating purifying is obtained compound L 1, and the structural formula of described compound L 1 is as follows:

Compound L 1:

Described compound L 1 is dissolved in N, in dinethylformamide, add the DIPEA that mol ratio is 6:3:3:3, I-hydroxybenzotriazole one water thing, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and dimethyl azanol hydrochloride, described compound L 1 is 1:3 with the mol ratio of dimethyl azanol hydrochloride, stirs 12 hours, and the cancellation that adds water is reacted, obtain the 3rd solution, by described 3rd solution separating purifying, obtain compound K, the structural formula of described compound K is as follows:

Compound K:

Under room temperature, described compound K is dissolved in tetrahydrofuran (THF), add the tetrahydrofuran solution that concentration is the ethynyl magnesium chloride of 0.6mol/L, the mol ratio of described compound K and described ethynyl magnesium chloride is 1:2, stir 20 hours, add saturated ammonium chloride solution cancellation reaction, obtain the 4th solution, described 4th solution separating purifying is obtained compound J, and the structural formula of described compound J is as follows:

Compound J:

It is the S-Alpine Borane solution removing tetrahydrofuran (THF) of 0.5mol/L by concentration, 0 DEG C adds described compound J, stir 6 hours, add acetaldehyde and stir cancellation in 30 minutes reaction, add thanomin and stir 1 hour, the mol ratio of described S-Alpine Borane, compound J, acetaldehyde and thanomin is 30.8:15.4:45:36, obtains the 5th solution, described 5th solution separating purifying is obtained Compound I, and the structural formula of described Compound I is as follows:

Compound I:

At 0 DEG C, described Compound I is dissolved in methylene dichloride, add triethylamine and Methanesulfonyl chloride, the mol ratio of described Compound I, triethylamine and Methanesulfonyl chloride is 1:4:2, stir 20 minutes, add saturated sodium bicarbonate solution cancellation reaction, obtain the 6th solution, described 6th solution separating purifying is obtained compound H, and the structural formula of described compound H is as follows:

Compound H:

Described compound H and glyoxylic acid ethyl ester are dissolved in the tetrahydrofuran (THF) that volume ratio is 3:1 and HMPA mixing solutions, at 0 DEG C, add [1, 1 '-bis-(diphenylphosphine) ferrocene] the sub-indium of palladium chloride dichloromethane complex and iodate, described compound H, glyoxylic acid ethyl ester, [1, 1 '-bis-(diphenylphosphine) ferrocene] mol ratio of the sub-indium of palladium chloride dichloromethane complex and iodate is 1.0:2.0:0.05:1.1, stir 8 hours, add shrend to go out reaction, obtain the 7th solution, described 7th solution separating purifying is obtained compound G, the structural formula of described compound G is as follows:

Compound G:

Under room temperature, described compound G is dissolved in methylene dichloride, add nitrobenzyl alcohol, 1, 3-two (2, 6-bis--isopropyl phenyl) imidazoles-2-subunit gold (I) muriate and silver hexafluoroantimonate, described compound G, to nitrobenzyl alcohol, 1, 3-two (2, 6-bis--isopropyl phenyl) mol ratio of imidazoles-2-subunit gold (I) muriate and described silver hexafluoroantimonate is 1.0:1.5:0.05:0.05, stir 10 minutes, obtain the 8th solution, by described 8th solution separating purifying, obtain compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a, the structural formula of described compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a is as follows:

Compound F 17-hydroxy-corticosterone: compound F 17-hydroxy-corticosterone a:

The mixing of described compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a is dissolved in acetonitrile, isobutenyl trimethyl silane and Trimethylsilyl trifluoromethanesulfonate is added at-40 DEG C, the mol ratio of the mixed solution of described compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a, isobutenyl trimethyl silane and Trimethylsilyl trifluoromethanesulfonate is 1.0:3.2:1.6, rise to room temperature, stir 8 hours, add saturated sodium bicarbonate solution cancellation reaction, obtain the 9th solution, described 9th solution separating purifying is obtained compd E, and the structural formula of described isobutenyl trimethyl silane and described compd E is as follows:

Isobutenyl trimethyl silane: compd E:

Described compd E is dissolved in tetrahydrofuran (THF), add dimethyl azanol hydrochloride, be cooled to-20 DEG C, add the tetrahydrofuran solution that concentration is the isopropylmagnesium chloride of 1.3mol/L, the mol ratio of described compd E, dimethyl azanol hydrochloride and isopropylmagnesium chloride is 1:3:6, stirs 20 minutes, add saturated ammonium chloride solution cancellation reaction, obtain the tenth solution, described tenth solution separating purifying is obtained compd E 1, and the structural formula of described compd E 1 is as follows:

Compd E 1:

By in described compd E 1 solution tetrahydrofuran (THF), the tetrahydrofuran solution that concentration is the 3-butenyl magnesium bromide of 0.5mol/L is added at 0 DEG C, described compd E 1 is 1:2 with the mol ratio of described 3-butenyl magnesium bromide, stirring at room temperature 30 minutes, add saturated ammonium chloride solution cancellation reaction, obtain the 11 solution, by described 11 solution separating purifying, obtain Compound D, the structural formula of described Compound D is as follows:

Compound D:

Wherein in an embodiment, described first solution separating purifying is obtained in the step of compound L, the method of described separation and purification is specially: by described first solution with ethyl acetate extraction, by organic phase anhydrous sodium sulfate drying, after filtering, removing tetrahydrofuran (THF) obtains oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:4 and the mixed solution of normal hexane be eluent, to described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compound L.

Wherein in an embodiment, described 9th solution separating purifying is obtained in the step of compd E, the method of described separation and purification is specially: by described 9th solution with dichloromethane extraction, get organic phase anhydrous sodium sulfate drying, after filtering, removing methylene dichloride obtains oily crude product, take volume ratio as the ethyl acetate of 1:40 ~ 1:60 and the mixed solution of ether be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compd E.

Wherein in an embodiment, described (1S, 2S)-pseudoephenamine is prepared by following steps:

Compound 1, ammonium formiate and methane amide are mixed and heated to 150 DEG C, stir 2 hours, be cooled to room temperature, filtration, washing, drying obtain compound 2, the mol ratio of described compound 1, ammonium formiate and methane amide is 1:0.2:20, and the structural formula of described compound 1 and described compound 2 is as follows:

Compound 1: compound 2:

At 0 DEG C, by sulfur oxychloride and described compound 2 mix and blend 10 minutes, rise to stirring at room temperature 30 minutes, add mixture of ice and water, be heated to reflux state and react 2 hours, be cooled to room temperature, add the aqueous sodium hydroxide solution that concentration is 6mol/L, stir 30 minutes, filter, wash, add ethyl alcohol recrystallization and obtain compound 3, the mol ratio of described sulfur oxychloride and compound 2 is 7:1, and the structural formula of described compound 3 is as follows:

Compound 3:

Diacetyl oxide and formic acid are mixed and heated to 60 DEG C, stir 1 hour, be cooled to room temperature, obtain mixed anhydride, described compound 3 being dissolved in volume ratio is, in the ether of 1:1 and the mixing solutions of tetrahydrofuran (THF), be cooled to-40 DEG C, add described mixed anhydride, stir 1 hour, rise to stirring at room temperature 2 hours, obtain the first reaction mixture, described first reaction mixture separation and purification is obtained compound 4, the mol ratio of described ammonium acetate, formic acid and compound 3 is 2:2.1:1, and the structural formula of described compound 4 is as follows:

Compound 4:

Described compound 4 being dissolved in volume ratio is in the ether of 1:1 and the mixing solutions of tetrahydrofuran (THF), be cooled to 0 DEG C, divide and add lithium aluminium hydride three times, the mol ratio of described compound 4 and lithium aluminium hydride is 1:2, rises to room temperature, stir 22 hours, be cooled to 0 DEG C, obtain the second reaction mixture, described second reaction mixture separation and purification is obtained described (1S, 2S)-pseudoephenamine, its structural formula is as follows:

(1S,2S)-pseudoephenamine：

The synthetic method of above-mentioned Cladiellin class natural product Pachycladin D is introduced sec.-propyl by myers chiral auxiliary and is generated compound L, 1, 3-two (2, 6-bis--isopropyl phenyl) imidazoles-2-subunit gold (I) muriate and silver hexafluoroantimonate catalyzed reaction, one step builds [6, 5] and member ring systems generates compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a, efficient simple, adopt Zhan 1B catalyst olefin metathesis reaction afterwards, high yield obtains Compound C, Compound C is utilized to obtain natural product Pachycladin D by the simple functional group conversions of a few step, operation is simple, each step productive rate is higher, can wide popularization and application.

Accompanying drawing explanation

Fig. 1 is the synthetic schemes of (1S, 2S)-pseudoephenamine of an embodiment;

Fig. 2 is the synthetic schemes of the Cladiellin class natural product Pachycladin D of an embodiment.

Embodiment

For enabling above-mentioned purpose of the present invention, feature and advantage become apparent more, are described in detail the specific embodiment of the present invention below in conjunction with accompanying drawing.Set forth a lot of detail in the following description so that fully understand the present invention.But the present invention can be much different from alternate manner described here to implement, those skilled in the art can when without prejudice to doing similar improvement when intension of the present invention, therefore the present invention is by the restriction of following public concrete enforcement.

Following step reaction is carried out all under nitrogen protection.

Refer to Fig. 1, the synthetic method of (1S, 2S)-pseudoephenamine of an embodiment, comprises the steps:

S110, by compound 1, ammonium formiate (HCO ₂nH ₄) and methane amide (HCONH ₂) be mixed and heated to 150 DEG C, stir 2 hours, be cooled to room temperature, filtration, washing, drying obtain compound 2, and the mol ratio of described compound 1, ammonium formiate and methane amide is 1:0.2:20.

Wherein, compound 1: buy in the resistance to Jilin Chemical of peace, No. CAS: 23190-16-1.

Compound 2:

Preferably, compound 1 with the mol ratio of ammonium formiate is: 0.206:0.041.

The reaction formula of step S110 is as follows:

In the present embodiment, filter, process that washing, drying obtain compound 2 is specially: adopt sand core funnel to filter, and with deionized water wash, then drying 1 hour at reduced pressure conditions, obtains compound 2.

S120, at 0 DEG C, by sulfur oxychloride (SOCl ₂) and described compound 2 mix and blend 10 minutes, rise to stirring at room temperature 30 minutes, add mixture of ice and water, be heated to backflow (reflux) state response 2 hours, be cooled to room temperature, add the aqueous sodium hydroxide solution that concentration is 6mol/L, stir 30 minutes, filter, wash, add ethyl alcohol recrystallization and obtain compound 3, the mol ratio of described sulfur oxychloride and compound 2 is 7:1.

Wherein, compound 3:

The reaction formula of step S120 is as follows:

In the present embodiment, filter, wash, add the process that ethyl alcohol recrystallization obtains compound 3 and be specially: adopt sand core funnel to filter, and with deionized water wash, then add ethyl alcohol recrystallization and obtain compound 3.

S130, by diacetyl oxide [(CH ₃cO) ₂o] and formic acid (HCOOH) be mixed and heated to 60 DEG C, stir 1 hour, be cooled to room temperature, obtain mixed anhydride, described compound 3 being dissolved in volume ratio is in the ether of 1:1 and the mixing solutions of tetrahydrofuran (THF), be cooled to-40 DEG C, add described mixed anhydride, stir 1 hour, rise to stirring at room temperature 2 hours, obtain the first reaction mixture, described first reaction mixture separation and purification is obtained compound 4, the mol ratio of described ammonium acetate, formic acid and compound 3 is 2:2.1:1.

Wherein, compound 4:

Above-mentioned first reaction mixture separation and purification is obtained compound 4, the method of separation and purification is specially: will be aqueous sodium hydroxide solution and the saturated sodium-chloride water solution extraction of 6mol/L by concentration in the first reaction mixture, get organic phase anhydrous magnesium sulfate drying, filter organic phase, decompression removing ether and tetrahydrofuran (THF), obtain compound 4.

Be appreciated that the method for separation and purification is not limited to aforesaid method, the method for separation and purification can be carried out to above-mentioned reaction product all passable.

The reaction formula of step S130 is as follows:

S140, described compound 4 is dissolved in the ether (Et that volume ratio is 1:1 ₂o) and in the mixing solutions of tetrahydrofuran (THF) (THF), be cooled to 0 DEG C, point add lithium aluminium hydride (LiAlH three times ₄), the mol ratio of described ammonium acetate, formic acid and compound 3 is 2:2.1:1, rises to room temperature, stir 22 hours, be cooled to 0 DEG C, obtain the second reaction mixture, described second reaction mixture separation and purification is obtained (1S, 2S)-pseudoephenamine.

Wherein, (1S, 2S)-pseudoephenamine:

Above-mentioned second reaction mixture separation and purification is obtained (1S, 2S)-pseudoephenamine, the method of separation and purification is specially: in above-mentioned second reaction mixture, slow dropping frozen water, concentration are aqueous sodium hydroxide solution and the water of 2mol/L, and sand core funnel filters, and gets organic phase anhydrous magnesium sulfate drying, filter organic phase, decompression removing ether and tetrahydrofuran (THF), obtain (1S, 2S)-pseudoephenamine.

The reaction formula of step S140 is as follows:

Be appreciated that the preparation method of (1S, 2S)-pseudoephenamine is not limited to step S110 ~ S140, additive method can also be adopted to prepare.

Refer to Fig. 2, the synthetic method of the Cladiellin class natural product Pachycladin D of an embodiment, comprises the following steps:

Under S150, room temperature, 5-hexynoic acid is dissolved in N, in dinethylformamide (DMF), add the N that mol ratio is 3:1.1:1.1:1.1, N-diisopropylethylamine (DIPEA), I-hydroxybenzotriazole one water thing (HOBT), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCl) and (1S, 2S)-pseudoephenamine, described 5-hexynoic acid and described (1S, 2S) mol ratio of-pseudoephenamine is 1:1.1, stir 12 hours, the cancellation that adds water is reacted, and obtains compound M.

Wherein, (1S, 2S)-pseudoephenamine: compound M:

The reaction formula of step S150 is as follows:

S160, described compound M is dissolved in tetrahydrofuran (THF), add lithium chloride (LiCl), be cooled to-78 DEG C, add lithium diisopropylamine (LDA), stir 1 hour, rise to stirring at room temperature half an hour, be cooled to-78 DEG C again, add isopropyl iodide, the mol ratio of described compound M, lithium chloride, lithium diisopropylamine and isopropyl iodide is 1:6:4:6, rises to room temperature, stir 10 ~ 12 hours, add saturated ammonium chloride solution cancellation reaction, obtain the first solution, described first solution separating purifying is obtained compound L.

Wherein, the structural formula of compound L is:

Described first solution separating purifying is obtained compound L, the method of separation and purification is specially: by described first solution with ethyl acetate extraction, get organic phase anhydrous sodium sulfate drying, after filtering, removing tetrahydrofuran (THF) obtains oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:4 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compound L.

The reaction formula of step S160 is as follows:

S170, described compound L to be dissolved in the mixing solutions of the trimethyl carbinol (t-BuOH) that volume ratio is 1:3 and water, to add the TBAH (n-Bu that mass percentage is 40% ₄nOH) aqueous solution, described compound L and described TBAH (n-Bu ₄nOH) mol ratio is 1:5, is heated to reflux state, reacts 36 hours, is cooled to room temperature, adjusts pH≤1, obtains the second solution, by described second solution separating purifying, obtain compound L 1.

Wherein, compound L 1:

Described second solution separating purifying is obtained compound L 1, and the method for separation and purification is specially: by described second solution extracted with diethyl ether, get organic phase anhydrous sodium sulfate drying, remove ether after filtration, obtain described compound L 1.

The reaction formula of step S170 is as follows:

S180, described compound L 1 is dissolved in N, in dinethylformamide, add the N that mol ratio is 6:3:3:3, N-diisopropylethylamine, I-hydroxybenzotriazole one water thing, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and dimethyl azanol hydrochloride, described compound L 1 is 1:3 with the mol ratio of dimethyl azanol hydrochloride, stirs 12 hours, and the cancellation that adds water is reacted, obtain the 3rd solution, described 3rd solution separating purifying is obtained compound K.

Wherein, compound K:

Described 3rd solution separating purifying is obtained compound K, the method of separation and purification is specially: by described 3rd solution with ethyl acetate extraction, get organic phase anhydrous sodium sulfate drying, N is removed after filtration, dinethylformamide obtains oily crude product, take volume ratio as the ethyl acetate of 1:4 ~ 1:8 and the mixed solution of sherwood oil be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compound K.

The reaction formula of step S180 is as follows:

Under S190, room temperature, described compound K is dissolved in tetrahydrofuran (THF), add the tetrahydrofuran solution that concentration is the ethynyl magnesium chloride of 0.6mol/L, the mol ratio of described compound K and described ethynyl magnesium chloride is 1:2, stir 20 hours, add saturated ammonium chloride solution cancellation reaction, obtain the 4th solution, described 4th solution separating purifying is obtained compound J.

Wherein, compound J:

Described 4th solution separating purifying is obtained compound J, the method of separation and purification is specially: by described 4th solution extracted with diethyl ether, get organic phase anhydrous sodium sulfate drying, after filtering, removing tetrahydrofuran (THF) obtains oily crude product, take volume ratio as the normal hexane of 1:30 and the mixed solution of ether be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compound J.

The reaction formula of step S190 is as follows:

S200, be the S-Alpine Borane solution removing tetrahydrofuran (THF) of 0.5mol/L by concentration, 0 DEG C adds described compound J, stir 6 hours, add acetaldehyde and stir cancellation in 30 minutes reaction, add thanomin and stir 1 hour, the mol ratio of described S-Alpine Borane, compound J, acetaldehyde and thanomin is 30.8:15.4:45:36, obtains the 5th solution, and described 5th solution separating purifying is obtained Compound I.

Wherein, Compound I:

S-Alpine Borane solution is bought in Sigma-Aldrich (Sigma-Aldrich) China Branch, and No. CAS: 42371-63-1.

Described 5th solution separating purifying is obtained Compound I, the method of separation and purification is specially: described 5th solution decompression concentrated removing acetaldehyde is obtained oily crude product, take volume ratio as the ethyl acetate of 1:20 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described Compound I.

The reaction formula of step S200 is as follows:

S210, at 0 DEG C, described Compound I is dissolved in methylene dichloride, add triethylamine and Methanesulfonyl chloride, the mol ratio of described Compound I, triethylamine and Methanesulfonyl chloride is 1:4:2, stir 20 minutes, add saturated sodium bicarbonate solution cancellation reaction, obtain the 6th solution, described 6th solution separating purifying is obtained compound H.

Wherein, compound H:

Described 6th solution separating purifying is obtained compound H, the method of separation and purification is: by described 6th solution with dichloromethane extraction, get organic phase anhydrous sodium sulfate drying, after filtering, removing methylene dichloride obtains oily crude product, take volume ratio as the ethyl acetate of 1:16 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compound H.

The reaction formula of step S210 is as follows:

S220, by described compound H and glyoxylic acid ethyl ester (OHCCO ₂et) be dissolved in the tetrahydrofuran (THF) and HMPA (HMPA) mixing solutions that volume ratio is 3:1, at 0 DEG C, add [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (Pd (dppf) C _l2* CH ₂cl ₂) and the sub-indium (InI) of iodate, described compound H, glyoxylic acid ethyl ester, [1,1 '-bis-(diphenylphosphine) ferrocene] mol ratio of the sub-indium of palladium chloride dichloromethane complex and iodate is 1.0:2.0:0.05:1.1, stir 8 hours, add shrend to go out reaction, obtain the 7th solution, described 7th solution separating purifying is obtained compound G.

Wherein, compound G:

[1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex is bought in lark prestige Science and Technology Ltd., and No. CAS: 95464-05-4.

Described 7th solution separating purifying is obtained compound G, the method of separation and purification is specially: by described 7th solution extracted with diethyl ether, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing tetrahydrofuran (THF) and HMPA obtain oily crude product, take volume ratio as the ethyl acetate of 1:32 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compound G.

The reaction formula of step S220 is as follows:

Under S230, room temperature, described compound G is dissolved in methylene dichloride, adds nitrobenzyl alcohol (p-NO ₂phCH ₂oH), two (2,6-, bis--isopropyl phenyl) imidazoles-2-subunit gold (I) muriate ((IPr) AuCl) of 1,3-and silver hexafluoroantimonate (AgSbF ₆), described compound G, to nitrobenzyl alcohol, 1,3-two (2,6-bis--isopropyl phenyl) mol ratio of imidazoles-2-subunit gold (I) muriate and described silver hexafluoroantimonate is 1.0:1.5:0.05:0.05, stir 10 minutes, obtain the 8th solution, described 8th solution separating purifying is obtained compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a.

Wherein, compound F 17-hydroxy-corticosterone: compound F 17-hydroxy-corticosterone a:

Two (2,6-, bis--isopropyl phenyl) imidazoles-2-subunit gold (I) muriate ((IPr) AuCl) of 1,3-is bought in lark prestige Science and Technology Ltd., and No. CAS: 852445-83-1.

Described 8th solution separating purifying is obtained compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a, the method of separation and purification is specially: described 8th solution decompression concentrated removing methylene dichloride is obtained oily crude product, take volume ratio as the ethyl acetate of 1:16 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain the mixture of compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a

The reaction formula of step S230 is as follows:

S240, the mixture of described compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a is dissolved in acetonitrile, isobutenyl trimethyl silane and Trimethylsilyl trifluoromethanesulfonate (TMSOTf) is added at-40 DEG C, the mol ratio of the mixture of described compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a, isobutenyl trimethyl silane and Trimethylsilyl trifluoromethanesulfonate is 1.0:3.2:1.6, rise to room temperature, stir 8 hours, add saturated sodium bicarbonate solution cancellation reaction, obtain the 9th solution, described 9th solution separating purifying is obtained compd E.

Wherein, isobutenyl trimethyl silane: isobutenyl trimethyl silane is bought in Sigma-Aldrich, and No. CAS: 18292-38-1.

Compd E:

Described 9th solution separating purifying is obtained compd E, the method of separation and purification is specially: by described 9th solution with dichloromethane extraction, get organic phase anhydrous sodium sulfate drying, after filtering, removing methylene dichloride obtains oily crude product, take volume ratio as the ethyl acetate of 1:40 ~ 1:60 and the mixed solution of ether be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compd E.

The reaction formula of step S240 is as follows:

S250, described compd E is dissolved in tetrahydrofuran (THF), add dimethyl azanol hydrochloride, be cooled to-20 DEG C, add the tetrahydrofuran solution of the isopropylmagnesium chloride (i-PrMgCl) that concentration is 1.3mol/L, the mol ratio of described compd E, dimethyl azanol hydrochloride and isopropylmagnesium chloride is 1:3:6, stirs 20 minutes, adds saturated ammonium chloride solution cancellation reaction, obtain the tenth solution, described tenth solution separating purifying is obtained compd E 1.

Wherein, compd E 1:

Described tenth solution separating purifying is obtained compd E 1, the method of separation and purification is specially: by described tenth solution with ethyl acetate extraction, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing tetrahydrofuran (THF) obtains oily crude product, take volume ratio as the ethyl acetate of 1:5 and the mixed solution of sherwood oil be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compd E 1.

The reaction formula of step S250 is as follows:

S260, described compd E 1 is dissolved in tetrahydrofuran (THF), the tetrahydrofuran solution of the 3-butenyl magnesium bromide of 0.5mol/L is added at 0 DEG C, described compd E 1 is 1:2 with the mol ratio of described 3-butenyl magnesium bromide, stirring at room temperature 30 minutes, add saturated ammonium chloride solution cancellation reaction, obtain the 11 solution, by described 11 solution separating purifying, obtain Compound D.

Wherein, Compound D:

Described 11 solution separating purifying is obtained Compound D, the method of separation and purification is specially: by described 11 solution with ethyl acetate extraction, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing tetrahydrofuran (THF) obtains oily crude product, take volume ratio as the ethyl acetate of 1:50 ~ 1:200 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described Compound D.

The reaction formula of step S260 is as follows:

S270, be dissolved in toluene by Compound D, be heated to reflux state, add Zhan 1B, the mol ratio of described Compound D and described Zhan 1B is 1:0.01 ~ 1:0.3, stirs 8 hours, obtains reaction solution, described reaction solution separation and purification is obtained Compound C.

Wherein, Compound C:

Zhan 1B is 1,3-two (2,4,6-trimethylphenyl)-4,5-glyoxalidine-2-base [2-isopropyl oxygen-5-(N, N dimethylamine sulphonyl) phenyl] methyl dichloro ruthenium, and its structural formula is: zhan 1B buys in Zannan Technology (Shanghai) Co., Ltd., and No. CAS: 918870-76-5.

Preferably, the mol ratio of Compound D and Zhan 1B is 1:0.1.

Described reaction solution separation and purification is obtained Compound C, and the method for separation and purification is specially: be the ethyl acetate of 1:20 ~ 1:50 and the mixed solution of normal hexane with volume ratio by described reaction solution be eluent, uses silica gel chromatographic column separating-purifying, obtains described Compound C.

Step S270 adopts the toluene of low toxicity to be solvent, and Zhan 1B catalyst Compound D replacement(metathesis)reaction, high yield obtains Compound C.

The reaction formula of step S270 is as follows:

S280, Compound C is dissolved in chloroform, be cooled to-12 DEG C, add the chloroformic solution that mass percentage is the metachloroperbenzoic acid of 75%, the mol ratio of described Compound C and described metachloroperbenzoic acid is 1:1.4, stir 22 hours at-12 DEG C, add saturated sodium bicarbonate solution cancellation and be obtained by reacting the first mixed solution, described first mixed solution separation and purification is obtained Compound C 1 and Compound C 2.

Wherein, Compound C 1: compound C 2:

Described first mixed solution separation and purification is obtained Compound C 1 and Compound C 2, and the method for separation and purification is specially: by described first mixed solution chloroform (CHCl ₃) extraction, get organic phase anhydrous magnesium sulfate drying, after filtering, removing chloroform obtains oily crude product, take volume ratio as the ethyl acetate of 1:10 ~ 1:20 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described Compound C 1 and Compound C 2.

The reaction formula of step S280 is as follows:

S290, by described Compound C 1 and Compound C 2 mixing be dissolved in Isosorbide-5-Nitrae-dioxane, add lithium hydroxide (LiOH) aqueous solution that concentration is 1.0mol/L, stir 1 hour, add the sal enixum (KHSO that concentration is 1.0mol/L ₄) aqueous solution stirs 15 minutes, then add the trifluoromethayl sulfonic acid scandium (Sc (OTf) that concentration is 0.04mol/L ₃) acetonitrile solution, described Compound C 1, Compound C 2, the mol ratio of lithium hydroxide, sal enixum and trifluoromethayl sulfonic acid scandium is 0.083:0.167:4.5:4.5:0.36, stir 6 hours, add saturated sodium bicarbonate solution cancellation and be obtained by reacting the second mixed solution, described second mixed solution separation and purification is obtained compd B.

Wherein, compd B:

Described second mixed solution separation and purification is obtained compd B, the method of separation and purification is specially: by described second mixed solution chloroform extraction, get organic phase anhydrous magnesium sulfate drying, removing 1 after filtering, 4-dioxane (Isosorbide-5-Nitrae-dioxane) obtains oily crude product, take volume ratio as the ethyl acetate of 1:1 ~ 1:3 and the mixed solution of normal hexane is eluent, to described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compd B.

The reaction formula of step S290 is as follows:

Be appreciated that the preparation method of compd B is not limited to step S150 ~ S290, other preparation methods can also be adopted.

S300, compd B is dissolved in methylene dichloride, TSIM is added under room temperature, the mol ratio of described compd B and described TSIM is 1:10, stir 1 hour, add saturated ammonium chloride solution cancellation reaction, obtain the first reaction solution, described first reaction solution separation and purification is obtained compound B-11.

Wherein, compound B-11:

Described first reaction solution separation and purification is obtained compound B-11, the method of separation and purification is specially: be extracted with ethyl acetate by the first reaction solution, get organic phase anhydrous sodium sulfate drying, methylene dichloride is removed after filtration, obtain oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:6 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compound B-11.

The reaction formula of step S300 is as follows:

S310, described compound B-11 is dissolved in toluene, add burgess reagent, 70 DEG C are stirred 20 minutes, be cooled to 0 DEG C, add the tetrahydrofuran solution that concentration is the tetrabutyl ammonium fluoride of 1.0mol/L, the mol ratio of described compound B-11, burgess reagent and tetrabutyl ammonium fluoride is 0.105:0.4:0.076, stir 15 minutes, add saturated ammonium chloride solution cancellation reaction, obtain the second reaction solution, described second reaction solution separation and purification is obtained compd A.

Wherein, compd A:

Described second reaction solution separation and purification is obtained compd A, the method of separation and purification is specially: in the second reaction solution, add silica gel, concentrating under reduced pressure removing tetrahydrofuran (THF) (THF), obtain oily crude product, take volume ratio as the ethyl acetate of 1:3 ~ 1:5 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compd A.

The reaction formula of step S310 is as follows:

S320, described compd A is dissolved in toluene, add the tetrahydrofuran solution that concentration is the methylmagnesium-chloride of 3.0mol/L, the mol ratio of described compd A and described methylmagnesium-chloride is 1:90, be heated to 100 DEG C, stir 30 minutes, be cooled to 0 DEG C, add saturated ammonium chloride solution cancellation reaction, obtain the 3rd reaction solution, described 3rd reaction solution separation and purification is obtained Compound C ladillisin.

Wherein, Compound C ladillisin:

Described 3rd reaction solution separation and purification is obtained Compound C ladillisin, the method of separation and purification is specially: be extracted with ethyl acetate by the 3rd reaction solution, get organic phase anhydrous sodium sulfate drying, toluene (toluene) and tetrahydrofuran (THF) (THF) is removed after filtration, obtain oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:6 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described Compound C ladillisin.

The reaction formula of step S320 is as follows:

S330, described Compound C ladillisin is dissolved in methylene dichloride, Manganse Dioxide is added under room temperature, the mol ratio of described Compound C ladillisin and described Manganse Dioxide is 1:60, stir 2 hours, obtain the 4th reaction solution, by described 4th reaction solution separation and purification, obtain natural product Pachycladin D.

Wherein, natural product Pachycladin D:

Described 4th reaction solution separation and purification is obtained natural product Pachycladin D, the method of separation and purification is specially: by the 4th reaction solution concentrating under reduced pressure removing methylene dichloride, obtain oily crude product, take volume ratio as the ethyl acetate of 1:5 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described natural product Pachycladin D.

The reaction formula of step S330 is as follows:

The synthetic method of above-mentioned Cladiellin class natural product Pachycladin D is introduced sec.-propyl by myers chiral auxiliary and is generated compound L, 1, 3-two (2, 6-bis--isopropyl phenyl) imidazoles-2-subunit gold (I) muriate and silver hexafluoroantimonate catalyzed reaction, one step builds [6, 5] and member ring systems generates compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a, efficient simple, adopt Zhan1B catalyst olefin metathesis reaction afterwards, high yield obtains Compound C, Compound C is utilized to obtain natural product Pachycladin D by the simple functional group conversions of a few step, operation is simple, each step productive rate is higher, can wide popularization and application.

It is below specific embodiment.

Embodiment 1

(1) synthesis of (1S, 2S)-pseudoephenamine

The structural formula of (1S, 2S)-pseudoephenamine is:

44g compound 1,2.6g ammonium formiate and 165ml methane amide are mixed and heated to 150 DEG C, stir 2 hours, be cooled to room temperature, adopt sand core funnel to filter, and use 250ml deionized water wash, then drying 1 hour at reduced pressure conditions, obtains compound 2.Concrete reaction formula is as follows:

At 0 DEG C, by 94ml sulfur oxychloride and compound 2 mix and blend 10 minutes, rise to stirring at room temperature 30 minutes, add 1100g mixture of ice and water to be heated to reflux state and to react 2 hours, be cooled to room temperature, add the aqueous sodium hydroxide solution that concentration is 6mol/L, stir 30 minutes, employing sand core funnel filters, and uses 200ml deionized water wash, adds 140ml ethyl alcohol recrystallization and obtains compound 3.Concrete reaction formula is as follows:

28.9ml diacetyl oxide and 12.9ml formic acid are mixed and heated to 60 DEG C, and stir 1 hour, cold going, to room temperature, obtains mixed anhydride.33g compound 3 being dissolved in volume ratio is, in the ether of 1:1 and the solution of tetrahydrofuran (THF), be cooled to-40 DEG C, add described mixed anhydride, stir 1 hour, rise to stirring at room temperature 2 hours, obtain the first reaction mixture.Be aqueous sodium hydroxide solution and the saturated sodium-chloride water solution extraction of 6mol/L by the first reaction mixture 250ml concentration, get organic phase anhydrous magnesium sulfate drying, filter organic phase, decompression removing ether and tetrahydrofuran (THF), obtain compound 4.Concrete reaction formula is as follows:

36g compound 4 being dissolved in volume ratio is, in the ether of 1:1 and the mixing solutions of tetrahydrofuran (THF), be cooled to 0 DEG C, 11.6g lithium aluminium hydride divided and add for three times, rise to room temperature, stir 22 hours, be cooled to 0 DEG C, obtain the second reaction mixture.In the second reaction mixture, slow dropping frozen water 12ml, concentration is aqueous sodium hydroxide solution 24ml and the water 36ml of 2mol/L, sand core funnel filters, get organic phase anhydrous magnesium sulfate drying, filter organic phase, decompression removing ether and tetrahydrofuran (THF), obtain (1S, 2S)-pseudoephenamine.Concrete reaction formula is as follows:

(2) synthesis of compound L

The structural formula of compound L is as follows:

Under room temperature condition, 8.0g is dissolved in 200mlN, in dinethylformamide, add 37mlN, N-diisopropylethylamine, 12g1-hydroxybenzotriazole one water thing, 15g1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and 17.6g (1S, 2S)-pseudoephenamine, stir 12 hours, the cancellation that adds water is reacted, and obtains compound M.Concrete reaction formula is as follows:

The Structural Identification of compound M:

¹H NMR(400MHz,CDCl ₃)δ7.37(d,J=7.3Hz,2H),7.33–7.21(m,8H),5.77(d,J=8.1Hz,1H),5.31(d,J=8.2Hz,1H),2.90(s,3H),2.51–2.36(m,2H),2.25–2.17(m,2H),1.96(t,J=2.4Hz,1H),1.79(dd,J=10.6,4.1Hz,2H). ¹³C NMR(101MHz,CDCl ₃)δ174.2,141.8,137.2,128.5,128.4,128.3,128.1,127.6,127.5,127.1,127.0,126.8,126.0,83.8,73.5,69.0,64.6,59.2,32.4,23.5,17.8.

21.0g compound M is dissolved in 300ml tetrahydrofuran (THF), add 16.5g lithium chloride, be cooled to-78 DEG C, add 130.8ml lithium diisopropylamine, stir 1 hour, rise to stirring at room temperature half an hour, then be cooled to-78 DEG C, add 38.6ml isopropyl iodide, slowly rise to room temperature, stir 10 ~ 12 hours, add saturated ammonium chloride solution cancellation reaction, obtain the first solution.By the first solution with ethyl acetate extraction, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing tetrahydrofuran (THF) obtains oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:4 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain compound L, productive rate 81%.Concrete reaction formula is as follows:

The Structural Identification of compound L:

¹h NMR (500MHz, CDCl ₃) δ=7.43 (d, J=7.5,2H), 7.27 – 7.40 (m, 8H), 5.94 (d, J=7.8,1H), 5.41 – 5.31 (m, 1H), 3.94 (s, 1H), 2.98 (s, 3H), 2.77 – 2.64 (m, 1H), 2.16 (d, J=16.7,1H), 1.99 (t, J=2.2,1H), 1.80 – 1.90 (m, 3H), 1.67 – 1.63 (m, 1H), 0.92 (d, J=6.7,3H), 0.86 (d, J=6.8,3H). ¹³c NMR (125MHz, CDCl ₃) δ=177.2,141.7,137.4,128.5,128.3,128.3,127.6,127.4,126.8,84.7,73.2,68.9,64.1,46.7,33.9,30.8,28.2,21.0,19.5,16.2.HRMS-ESI:C ₂₄h ₃₀nO ₂[M+H ⁺] molecular weight calculated value: 364.2271; Molecular weight measured value: 364.2271. [α] _d ²⁵=+180.7 (c=1.0, CHCl ₃)

(3) synthesis of compound K

The structural formula of compound K is as follows:

21.0g compound L being dissolved in volume ratio is in the trimethyl carbinol of 1:3 and the mixing solutions of water, add the TBAH aqueous solution that 151ml mass percentage is 40%, be heated to reflux state and react 36 hours, be cooled to room temperature, adjust pH≤1, obtain the second solution.By the second solution extracted with diethyl ether, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing ether, obtains compound L 1.Concrete reaction formula is as follows:

The Structural Identification of compound L 1:

¹H NMR(400MHz,CDCl ₃)δ10.61(s,1H),2.37(m,1H),2.29(m,1H),2.20(m,1H),1.98(m,,2H),1.86(m,1H),1.74(m,1H),0.99(dd,J=6.8,2.6Hz,6H). ¹³C NMR(100MHz,CDCl ₃)δ181.5,83.3,68.9,50.9,30.2,27.5,20.1,19.7,16.8。

The compound L 1 of above-mentioned preparation is dissolved in 200mlN, in dinethylformamide, add 41mlN, N-diisopropylethylamine, 18g1-hydroxybenzotriazole one water thing, 22.4g1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and 11.4g dimethyl azanol hydrochloride, stir 12 hours, the cancellation that adds water is reacted, and obtains the 3rd solution.

By the 3rd solution with ethyl acetate extraction, get organic phase anhydrous sodium sulfate drying, filter organic phase, step-down concentrated removing N, dinethylformamide obtains oily crude product, take volume ratio as the ethyl acetate of 1:4 ~ 1:8 and the mixed solution of sherwood oil is eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain compound K, productive rate 66%.Concrete reaction formula is as follows:

The Structural Identification of compound K:

¹h NMR (500MHz, CDCl ₃) δ=3.69 (s, 3H), 3.17 (s, 3H), 2.81 (s, 1H), 2.32 – 2.13 (m, 1H), 2.08 – 1.97 (m, 1H), 1.92 (t, J=2.6,1H), 1.94 – 1.85 (m, 2H), 1.74 – 1.63 (m, 1H), 0.91 (dd, J=13.2,6.8,6H). ¹³c NMR (126MHz, CDCl ₃) δ=176.4,84.2,68.4,61.2,45.9,32.0,30.5,27.9,20.81,19.6,16.6.HRMS-ESI:C ₁₁h ₂₀nO ₂[M+H ⁺] molecular weight calculated value: 198.1489; Molecular weight measured value: 198.1487

(4) synthesis of compound J

The structural formula of compound J is as follows:

Under room temperature condition, 4.0g compound K is dissolved in 150ml tetrahydrofuran (THF), adds the tetrahydrofuran solution that 67ml concentration is the ethynyl magnesium chloride of 0.6mol/L, stir 20 hours, add saturated ammonium chloride solution cancellation reaction, obtain the 4th solution.

By the 4th solution extracted with diethyl ether, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing tetrahydrofuran (THF) obtains oily crude product, take volume ratio as the normal hexane of 1:30 and the mixed solution of ether be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain compound J, productive rate 90%.Concrete reaction formula is as follows:

The Structural Identification of compound J:

¹H NMR(500MHz,CDCl ₃)δ=3.25(s,1H),2.54(ddd,J=9.9,6.4,3.2,1H),2.29–2.21(m,1H),2.16(tt,J=9.6,4.7,1H),2.08(ddd,J=16.8,7.9,2.6,1H),2.02–1.94(m,2H),1.77–1.66(m,1H),0.96(dd,J=34.5,6.8,7H). ¹³C NMR(126MHz,CDCl ₃)δ=190.0,83.3,81.4,79.0,69.1,59.6,29.7,26.0,20.7,19.1,16.8.

(5) synthesis of Compound I

The structural formula of Compound I is as follows:

Be the S-Alpine Borane solution removing tetrahydrofuran (THF) of 0.5mol/L by 61.6ml concentration, 0 DEG C adds 2.5g compound J, stirs 6 hours, adds 2.5ml acetaldehyde and stirs cancellation in 30 minutes reaction, add 2.3ml thanomin and stir 1 hour, obtain the 5th solution.By concentrated for the 5th solution decompression removing organic solvent, obtaining oily crude product, take volume ratio as the ethyl acetate of 1:20 and the mixed solution of normal hexane is eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtains Compound I, productive rate 68%.Concrete reaction formula is as follows:

The Structural Identification of Compound I:

¹H NMR(500MHz,CDCl ₃)δ4.45(dd,J=5.7,2.2Hz,1H),2.49(d,J=2.2Hz,1H),2.37–2.32(m,2H),2.05–1.99(m,2H),1.97(t,J=2.6Hz,1H),1.78–1.67(m,2H),1.60–1.53(m,1H),0.97(d,J=6.9Hz,3H),0.91(d,J=6.9Hz,3H). ¹³C NMR(125MHz,CDCl ₃)δ=84.7,84.6,73.9,68.5,64.3,48.7,28.2,25.9,20.9,18.7,18.0.

(6) synthesis of compound H

The structural formula of compound H is as follows:

At 0 DEG C, 1.5g Compound I is dissolved in 50ml methylene dichloride, adds 5.0ml triethylamine and 2.1g Methanesulfonyl chloride, stir 20 minutes, add saturated sodium bicarbonate solution cancellation reaction, obtain the 6th solution.

By the 6th solution with dichloromethane extraction, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing methylene dichloride obtains oily crude product, take volume ratio as the ethyl acetate of 1:16 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain compound H, productive rate 90%.Concrete reaction formula is as follows:

The Structural Identification of compound H:

¹h NMR (400MHz, CDCl ₃) δ=5.27 (dd, J=4.5,2.2,1H), 3.13 (s, 3H) 2.76 (d, J=2.3,1H), 2.33 (td, J=7.3,2.6,2H), 2.04 – 1.98 (m, 1H), 1.97 (t, J=2.6,1H), 1.83 – 1.73 (m, 3H), 0.98 (dd, J=11.7,6.9,6H). ¹³c NMR (100MHz, CDCl ₃) δ=83.7,79.1,77.9,73.2,69.0,47.6,39.4,28.1,26.0,20.4,19.0,17.6.HRMS-ESI:C ₁₂h ₁₈o ₃sNa [M+Na ⁺] molecular weight calculated value: 265.0869; Molecular weight measured value: 265.0865.

(7) synthesis of compound G

The structural formula of compound G is as follows:

3.0g compound H and 1.93g glyoxylic acid ethyl ester are dissolved in the tetrahydrofuran (THF) and HMPA mixing solutions that volume ratio is 3:1, at 0 DEG C, add 505mg [1,1 '-bis-(diphenylphosphine) ferrocene] the sub-indium of palladium chloride dichloromethane complex and 3.2g iodate, stir 8 hours, add shrend to go out reaction, obtain the 7th solution.

By the 7th solution extracted with diethyl ether, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing tetrahydrofuran (THF) and HMPA obtain oily crude product, take volume ratio as the ethyl acetate of 1:32 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain compound G, productive rate 65% and compound Ga, productive rate 25%.Concrete reaction formula is as follows:

The Structural Identification of compound G:

¹h NMR (500MHz, CDCl ₃) δ 4.30 – 4.19 (m, 3H), 2.98 (d, J=7.8Hz, 1H), 2.84 (dt, J=5.8,2.8Hz, 1H), 2.37 – 2.21 (m, 2H), 2.14 (d, J=2.6Hz, 1H), 1.97 (t, J=2.6Hz, 1H), 1.89 – 1.77 (m, 2H), 1.72 – 1.66 (m, 1H), 1.66 – 1.60 (m, 1H), 1.32 (t, J=7.2Hz, 3H), 0.92 (dd, J=6.8,2.6Hz, 6H). ¹³c NMR (125MHz, CDCl ₃) δ=173.1,84.6,81.7,72.9,72.9,68.5,61.8,41.1,37.5,30.0,28.0,19.9,18.6,17.5,14.1.HRMS-ESI:C ₁₅h ₂₃o ₃[M+H ⁺] molecular weight calculated value: 251.1642; Molecular weight measured value: 251.1648.

(8) synthesis of compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a

Compound F 17-hydroxy-corticosterone: compound F 17-hydroxy-corticosterone a:

Under room temperature condition, 1.0g compound G is dissolved in 600ml methylene dichloride, adds 900mg to nitrobenzyl alcohol, two (2,6-, bis--isopropyl phenyl) imidazoles-2-subunit gold (I) muriate of 124mg1,3-and 68mg silver hexafluoroantimonate, stir 10 minutes, obtain the 8th solution.Described 8th solution decompression concentrated removing methylene dichloride is obtained oily crude product, take volume ratio as the ether of 1:16 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain the mixture of compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a, overall yield 65%.

The Structural Identification of compound F 17-hydroxy-corticosterone:

¹h NMR (400MHz, CDCl ₃) δ=8.20 (d, J=8.7, 2H), 7.56 (d, J=8.6, 2H), 5.30 (s, 1H), 5.02 (d, J=12.8, 1H), 4.86 (s, 1H), 4.79 (s, 1H), 4.55 (d, J=12.8, 1H), 4.35 (d, J=9.0, 1H), 4.21 – 4.08 (m, 2H), 3.38 – 3.27 (m, 1H), 2.93 (d, J=7.0, 1H), 2.38 (dt, J=13.5, 4.8, 1H), 2.09 – 1.99 (m, 1H), 1.93 – 1.84 (m, 1H), 1.49 – 1.40 (m, 2H), 1.30 – 1.26 (m, 1H), 1.22 (t, J=7.2, 3H), 0.89 (dd, J=5.6, 3.6, 6H). ¹³cNMR (100MHz, CDCl ₃) δ=172.9,147.4,146.0,144.0,128.1,123.6,109.3,105.4,77.4,67.5,61.1,52.4,43.4,43.0,33.7,30.6,25.9,21.5,21.1,14.0.HRMS-ESI:C ₂₂h ₂₉nO ₆na [M+Na ⁺] molecular weight calculated value: 426.1887, molecular weight measured value: 426.1893

The Structural Identification of compound F 17-hydroxy-corticosterone a:

¹h NMR (400MHz, CDCl ₃) δ=8.17 (d, J=8.7, 2H), 7.55 (d, J=8.7, 2H), 5.18 (d, J=5.9, 1H), 5.00 (d, J=13.5, 1H), 4.86 (d, J=0.9, 2H), 4.72 (d, J=13.5, 1H), 4.45 (d, J=1.6, 1H), 4.23 – 4.14 (m, 2H), 3.00 (t, J=6.4, 1H), 2.46 (ddd, J=10.4, 7.2, 1.5, 1H), 2.33 (dt, J=13.8, 3.6, 1H), 2.05 – 1.92 (m, 1H), 1.87 – 1.82 (m, 1H), 1.76 – 1.67 (m, 1H), 1.38 – 1.34 (m, 1H), 1.25 (t, J=7.1, 3H), 1.12 (ddd, J=24.8, 12.7, 3.4, 1H), 0.98 (d, J=6.9, 3H), 0.81 (d, J=6.8, 3H). ¹³c NMR (100MHz, CDCl ₃) δ=172.4,147.2,146.0,143.4,127.7,123.4,112.0,107.0,80.8,69.0,61.0,50.7,47.3,42.1,31.6,28.6,24.7,21.5,16.0,14.1.HRMS-ESI:C ₂₂h ₂₉nO ₆na [M+Na ⁺] molecular weight calculated value: 426.1887, molecular weight measured value: 426.1878.

(9) synthesis of compd E

The structural formula of compd E is as follows:

The mixture of 1.0g compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a is dissolved in 25ml acetonitrile, add 1.4ml isobutenyl trimethyl silane and 0.7ml Trimethylsilyl trifluoromethanesulfonate at-40 DEG C, rise to room temperature, stir 8 hours, add saturated sodium bicarbonate solution cancellation reaction, obtain the 9th solution.

By the 9th solution with dichloromethane extraction, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing methylene dichloride obtains oily crude product, take volume ratio as the ethyl acetate of 1:40 ~ 1:60 and the mixed solution of ether be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain compd E, productive rate 60%.Concrete reaction formula is as follows:

The Structural Identification of compd E:

¹h NMR (500MHz, CDCl ₃) δ 4.84 (d, J=11.5Hz, 2H), 4.81 (t, J=1.9Hz, 1H), 4.75 (s, 1H), 4.44 (s, 1H), 4.17 (dd, J=14.3, 7.2Hz, 2H), 4.15 – 4.09 (m, 1H), 2.64 (dd, J=10.2, 6.7Hz, 1H), 2.38 (dd, J=14.5, 9.4Hz, 1H), 2.31 (s, 1H), 2.30 – 2.27 (m, 1H), 2.24 (dd, J=11.8, 6.8Hz, 1H), 2.10 (ddd, J=13.8, 11.9, 1.8Hz, 1H), 1.98 – 1.91 (m, 1H), 1.79 (m, 4H), 1.52 – 1.44 (m, 1H), 1.28 (t, J=7.1Hz, 3H), 1.11 – 1.02 (m, 1H), 1.00 (d, J=7.0Hz, 3H), 0.79 (d, J=6.9Hz, 3H). ¹³c NMR (125MHz, CDCl ₃) δ=173.5,145.1,143.6,111.8,111.7,80.7,80.2,60.7,51.7,49.5,42.7,42.2,31.5,28.3,25.5,22.9,21.63,15.4,14.2.HRMS-ESI:C ₁₉h ₃₁o ₃[M+H ⁺] molecular weight calculated value: 307.2268, molecular weight measured value: 307.2267.

(10) synthesis of Compound D

The structural formula of Compound D is as follows:

537mg compd E is dissolved in 15ml tetrahydrofuran (THF), adds 510mg dimethyl azanol hydrochloride, be cooled to-20 DEG C, add the tetrahydrofuran solution that 8.1ml concentration is the isopropylmagnesium chloride of 1.3mol/L, stir 20 minutes, add saturated ammonium chloride solution cancellation reaction, obtain the tenth solution.

By the tenth solution with ethyl acetate extraction, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing tetrahydrofuran (THF) obtains oily crude product, take volume ratio as the ethyl acetate of 1:5 and the mixed solution of sherwood oil be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain compd E 1.Concrete reaction formula is as follows:

The Structural Identification of compd E 1:

¹h NMR (500MHz, CDCl ₃) δ 4.86 – 4.71 (m, 5H), 4.13 (td, J=9.9,1.6Hz, 1H), 3.66 (s, 3H), 3.17 (s, 3H), 2.76 (dd, J=10.0,6.5Hz, 1H), 2.56 – 2.46 (m, 1H), 2.31 – 2.22 (m, 3H), 2.16 – 2.06 (m, 1H), 1.92 – 1.83 (m, 1H), 1.76 (s, 3H), 1.49 (t, J=12.1Hz, 1H), 1.05 (m, J=26.4,13.2,3.5Hz, 1H), 0.99 (d, J=6.9Hz, 3H), 0.75 (d, J=6.8Hz, 3H). ¹³c NMR (125MHz, CDCl ₃) δ=173.5,145.3,144.0,111.4,80.0,79.4,61.0,51.6,48.1,42.5,41.9,32.4,31.4,28.0,25.4,22.9,21.8,15.4.HRMS-ESIC ₁₉h ₃₂nO ₃[M+H ⁺] molecular weight calculated value: 322.2377; Molecular weight measured value: 322.2372.

0.43g compd E 1 is dissolved in 15ml tetrahydrofuran (THF), adds at 0 DEG C the tetrahydrofuran solution that 6.0ml concentration is the 3-butenyl magnesium bromide of 0.5mol/L, stirring at room temperature 30 minutes, add saturated ammonium chloride solution cancellation reaction, obtain the 11 solution.

By the 11 solution with ethyl acetate extraction, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing tetrahydrofuran (THF) obtains oily crude product, take volume ratio as the ethyl acetate of 1:50 ~ 200 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain Compound D, productive rate 76%.Concrete reaction formula is as follows:

(11) synthesis of Compound C

The structural formula of Compound C is as follows:

170mg Compound D is dissolved in 600ml toluene, is heated to reflux state, add 3.82mgZhan1B, stir 8 hours, obtain reaction solution.

Be the ethyl acetate of 1:20 ~ 1:50 and the mixed solution of normal hexane with volume ratio by reaction solution be eluent, use silica gel chromatographic column separating-purifying, obtain Compound C, productive rate 70%.Concrete reaction formula is as follows:

(12) synthesis of compd B

The structural formula of compd B is as follows:

120mg Compound C is dissolved in 32ml chloroform, is cooled to-12 DEG C, add the chloroformic solution that 170mg mass percentage is the metachloroperbenzoic acid of 75%, stir 22 hours at-12 DEG C, add saturated sodium bicarbonate solution cancellation and be obtained by reacting the first mixed solution.

By the first mixed solution chloroform extraction, get organic phase anhydrous magnesium sulfate drying, filter organic phase, concentrating under reduced pressure removing chloroform obtains oily crude product, take volume ratio as the ethyl acetate of 1:10 ~ 1:20 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described Compound C 1 and Compound C 2.Concrete reaction formula is as follows:

80mg Compound C 1 and Compound C 2 mixing are dissolved in 6ml1, in 4-dioxane, add the lithium hydroxide aqueous solution that 4.5ml concentration is 1.0mol/L, stir 1 hour, adding 4.5ml concentration is that the aqueous potassium hydrogen sulfate of 1.0mol/L stirs 15 minutes, add the acetonitrile solution that 183mg concentration is the trifluoromethayl sulfonic acid scandium of 0.04mol/L again, stir 6 hours, add saturated sodium bicarbonate solution cancellation and obtain the second mixed solution.

By the second mixed solution chloroform extraction, get organic phase anhydrous magnesium sulfate drying, filter organic phase, concentrating under reduced pressure removing Isosorbide-5-Nitrae-dioxane (Isosorbide-5-Nitrae-dioxane) obtains oily crude product, take volume ratio as the ethyl acetate of 1:1 ~ 1:3 and the mixed solution of normal hexane be eluent, to described oily crude product purified by silica gel chromatographic column separating-purifying, obtain compd B, productive rate 41%.Concrete reaction formula is as follows:

(13) synthesis of compd A

The structural formula of compd A is as follows:

40mg compd B is dissolved in 10ml methylene dichloride, under room temperature condition, adds 0.17g TSIM, stir 1 hour, add saturated ammonium chloride solution cancellation reaction, obtain the first reaction solution.

First reaction solution is extracted with ethyl acetate, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing methylene dichloride, obtain oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:6 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain compound B-11.Concrete reaction formula is as follows:

The Structural Identification of compound B-11:

¹h NMR (300MHz, CDCl ₃) δ 4.71 (t, J=2.0Hz, 1H), 4.67 (s, 1H), 4.16 (dd, J=9.1,4.8Hz, 1H), 4.12 – 4.03 (m, 1H), 3.78 (s, 1H), 3.62 (t, J=8.2Hz, 1H), 2.34 – 2.20 (m, 5H), 2.03 (m, J=4.5Hz, 3H), 1.95 – 1.85 (m, 2H), 1.85 – 1.69 (m, 2H), 1.50 (s, 3H), 1.25 – 1.16 (m, 1H), 1.07 – 0.99 (m, 1H), 0.94 (d, J=7.0Hz, 3H), 0.77 (d, J=6.8Hz, 3H), 0.15 (s, 9H). ¹³c NMR (75MHz, CDCl ₃) δ 148.3,109.6,109.1,88.7,85.5,81.6,74.5,47.5,44.4,43.1,42.3,38.6,31.6,31.4,28.8,26.0,24.9,21.7,15.5,1.4.HRMS-(APCI): C ₂₂h ₃₈o ₄si [M+H ⁺] molecular weight calculated value: 394.2539, molecular weight measured value: 394.2539

41mg compound B-11 is dissolved in 6ml toluene, add 100mg burgess reagent, 70 DEG C are stirred 20 minutes, coldly go to 0 DEG C, add the tetrahydrofuran solution that 0.076ml concentration is the tetrabutyl ammonium fluoride of 1.0mol/L, stir 15 minutes, add saturated ammonium chloride solution cancellation reaction, obtain the second reaction solution.

Second reaction solution is extracted with ethyl acetate, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing tetrahydrofuran (THF), obtaining oily crude product, take volume ratio as the ethyl acetate of 1:3 ~ 1:5 and the mixed solution of normal hexane is eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain compd A, productive rate 72%.Concrete reaction formula is as follows:

The Structural Identification of compd A:

¹h NMR (400MHz, CDCl ₃) δ 5.56 (dd, J=6.3, 1.3Hz, 1H), 5.14 (t, J=1.9Hz, 1H), 4.95 (t, J=2.0Hz, 1H), 4.89 (dd, J=8.5, 6.6Hz, 1H), 4.68 (dd, J=4.8, 2.6Hz, 1H), 4.59 (s, 1H), 4.30 – 4.26 (m, 1H), 4.07 (dt, J=8.6, 3.1Hz, 1H), 3.89 (s, 1H), 3.86 (s, 1H), 3.59 (t, J=7.9Hz, 1H), 3.47 (t, J=8.2Hz, 1H), 2.91 (dd, J=15.9, 2.9Hz, 1H), 2.44 – 2.37 (m, 1H), 2.35 – 2.31 (m, 1H), 2.31 – 2.23 (m, 1H), 2.17 – 2.09 (m, 1H), 2.04 (m, 1H), 1.80 (m, 1H), 1.71 (dd, J=12.8, 3.4Hz, 1H), 1.30 – 1.22 (m, 1H), 1.08 – 0.99 (m, 1H), 0.96 (d, J=7.0Hz, 3H), 0.77 (d, J=6.9Hz, 3H). ¹³cNMR (100MHz, CDCl ₃) δ=147.7,145.8,120.0,110.1,107.2,87.9,83.7,81.4,47.3,45.3,43.3,38.5,36.3,31.5,29.0,27.8,25.0,21.9,15.6.HRMS-(APCI): C ₁₉h ₂₉o ₃[M+H ⁺] molecular weight calculated value: 305.2111, molecular weight measured value: 305.2106.

(14) synthesis of Compound C ladillisin

The structural formula of Compound C ladillisin is as follows:

15.0mg compd A is dissolved in 10ml toluene, adds the tetrahydrofuran solution that 1.5ml concentration is the methylmagnesium-chloride of 3.0mol/L, be heated to 100 DEG C, stir 30 minutes, be cooled to 0 DEG C, add saturated ammonium chloride solution cancellation reaction, obtain the 3rd reaction solution.

3rd reaction solution is extracted with ethyl acetate, get organic phase anhydrous sodium sulfate drying, filter organic phase, concentrating under reduced pressure removing toluene and tetrahydrofuran (THF), obtaining oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:6 and the mixed solution of normal hexane is eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described Compound C ladillisin, productive rate 93%.Concrete reaction formula is as follows:

(15) synthesis of natural product Pachycladin D

The structural formula of natural product Pachycladin D is as follows:

6mg Compound C ladillisin is dissolved in methylene dichloride, under room temperature, adds 97mg Manganse Dioxide, stir 2 hours, obtain the 4th reaction solution.

By the 4th reaction solution concentrating under reduced pressure removing methylene dichloride, obtaining oily crude product, take volume ratio as the ethyl acetate of 1:5 and the mixed solution of normal hexane is eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described natural product Pachycladin D, productive rate 83%.Concrete reaction formula is as follows:

Embodiment 2

In the synthetic method of the natural product Pachycladin D of embodiment 2, (1S, 2S)-pseudoephenamine, compound L, compound K, compound J, Compound I, compound H, compound G, compound F 17-hydroxy-corticosterone are identical with embodiment 1 with the preparation of compound F 17-hydroxy-corticosterone a, compd E, Compound D, compd B, compd A, Compound C ladillisin and natural product Pachycladin D, and difference is:

(11) synthesis of Compound C

The structural formula of Compound C is as follows:

170mg Compound D is dissolved in toluene, is heated to reflux state, add 114.5mgZhan 1B, stir 8 hours, obtain reaction solution.

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

1. a synthetic method of natural product Pachycladin D, is characterized in that, comprises the following steps:

Compd B:

Compound B-11:

Compd A:

Compound C ladillisin:

Natural product Pachycladin D:

2. the synthetic method of natural product Pachycladin D as claimed in claim 1, it is characterized in that, described first reaction solution separation and purification is obtained in the step of compound B-11, the method of described separation and purification is specially: be extracted with ethyl acetate by described first reaction solution, get organic phase anhydrous sodium sulfate drying, after filtering, removing methylene dichloride obtains oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:6 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compound B-11.

3. the synthetic method of natural product Pachycladin D as claimed in claim 1, it is characterized in that, described 3rd reaction solution separation and purification is obtained in the step of Compound C ladillisin, the method of described separation and purification is specially: be extracted with ethyl acetate by institute the 3rd reaction solution, get organic phase anhydrous sodium sulfate drying, after filtering, removing toluene and ethyl acetate obtain oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:6 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described Compound C ladillisin.

4. the synthetic method of natural product Pachycladin D as claimed in claim 1, it is characterized in that, described compd B is prepared by following steps:

Compound C:

Compound C 1:

Compound C 2:

Described Compound C 1 and Compound C 2 mixing are dissolved in 1, in 4-dioxane, add the lithium hydroxide aqueous solution that concentration is 1.0mol/L, stir 1 hour, adding concentration is that the aqueous potassium hydrogen sulfate of 1.0mol/L stirs 15 minutes, add the acetonitrile solution that concentration is the trifluoromethayl sulfonic acid scandium of 0.04mol/L again, described Compound C 1, Compound C 2, lithium hydroxide, the mol ratio of sal enixum and trifluoromethayl sulfonic acid scandium is 0.083:0.167:4.5:4.5:0.36, stir 6 hours, add saturated sodium bicarbonate solution cancellation and be obtained by reacting the second mixed solution, described second mixed solution separation and purification is obtained compd B, the structural formula of described compd B is as follows:

Compd B:

5. the synthetic method of natural product Pachycladin D as claimed in claim 4, it is characterized in that, described first mixed solution separation and purification is obtained in the step of Compound C 1 and Compound C 2, the method of described separation and purification is specially: by described first mixed solution chloroform extraction, get organic phase anhydrous magnesium sulfate drying, after filtering, removing chloroform obtains oily crude product, take volume ratio as the ethyl acetate of 1:10 ~ 1:20 and the mixed solution of normal hexane be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described Compound C 1 and Compound C 2.

6. the synthetic method of natural product Pachycladin D as claimed in claim 4, it is characterized in that, described Compound C is prepared by following steps:

Compound D:

Zhan 1B:

Compound C:

7. the synthetic method of natural product Pachycladin D as claimed in claim 6, it is characterized in that, described Compound D is prepared by following steps:

(1S,2S)-pseudoephenamine：

Compound M:

Compound L:

Compound L 1:

Described compound L 1 is dissolved in N, in dinethylformamide, add DIPEA, I-hydroxybenzotriazole one water thing, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and dimethyl azanol hydrochloride that mol ratio is 6:3:3:3, described compound L 1 is 1:3 with the mol ratio of dimethyl azanol hydrochloride, stir 12 hours, the cancellation that adds water is reacted, and obtains the 3rd solution, by described 3rd solution separating purifying, obtain compound K, the structural formula of described compound K is as follows:

Compound K:

Compound J:

Compound I:

Compound H:

Described compound H and glyoxylic acid ethyl ester are dissolved in the tetrahydrofuran (THF) that volume ratio is 3:1 and HMPA mixing solutions, at 0 DEG C, add [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride dichloromethane complex and the sub-indium of iodate, described compound H, glyoxylic acid ethyl ester, [1, two (diphenylphosphine) ferrocene of 1'-] mol ratio of palladium chloride dichloromethane complex and the sub-indium of iodate is 1.0:2.0:0.05:1.1, stir 8 hours, add shrend to go out reaction, obtain the 7th solution, described 7th solution separating purifying is obtained compound G, the structural formula of described compound G is as follows:

Compound G:

Under room temperature, described compound G is dissolved in methylene dichloride, add nitrobenzyl alcohol, 1, 3-two (2, 6-bis--isopropyl phenyl) imidazoles-2-subunit gold (I) muriate and silver hexafluoroantimonate, described compound G, to nitrobenzyl alcohol, 1, 3-two (2, 6-bis--isopropyl phenyl) mol ratio of imidazoles-2-subunit gold (I) muriate and described silver hexafluoroantimonate is 1.0:1.5:0.05:0.05, stir 10 minutes, obtain the 8th solution, by described 8th solution separating purifying, obtain the mixture of compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a, the structural formula of described compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a is as follows:

Compound F 17-hydroxy-corticosterone:

Compound F 17-hydroxy-corticosterone a:

The mixture of described compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a is dissolved in acetonitrile, isobutenyl trimethyl silane and Trimethylsilyl trifluoromethanesulfonate is added at-40 DEG C, the mol ratio of the mixture of described compound F 17-hydroxy-corticosterone and compound F 17-hydroxy-corticosterone a, isobutenyl trimethyl silane and Trimethylsilyl trifluoromethanesulfonate is 1.0:3.2:1.6, rise to room temperature, stir 8 hours, add saturated sodium bicarbonate solution cancellation reaction, obtain the 9th solution, described 9th solution separating purifying is obtained compd E, and the structural formula of described isobutenyl trimethyl silane and described compd E is as follows:

Isobutenyl trimethyl silane:

Compd E:

Compd E 1:

By in described compd E 1 solution tetrahydrofuran (THF), the tetrahydrofuran solution that concentration is the 3-butenyl magnesium bromide of 0.5mol/L is added at 0 DEG C, described compd E 1 is 1:2 with the mol ratio of described 3-butenyl magnesium bromide, stirring at room temperature 30 minutes, add saturated ammonium chloride solution cancellation reaction, obtain the 11 solution, described 11 solution separating purifying is obtained Compound D, and the structural formula of described Compound D is as follows:

Compound D:

8. the synthetic method of natural product Pachycladin D as claimed in claim 7, it is characterized in that, described first solution separating purifying is obtained in the step of compound L, the method of described separation and purification is specially: by described first solution with ethyl acetate extraction, by organic phase anhydrous sodium sulfate drying, after filtering, removing tetrahydrofuran (THF) obtains oily crude product, take volume ratio as the ethyl acetate of 1:2 ~ 1:4 and the mixed solution of normal hexane be eluent, to described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compound L.

9. the synthetic method of natural product Pachycladin D as claimed in claim 7, it is characterized in that, described 9th solution separating purifying is obtained in the step of compd E, the method of described separation and purification is specially: by described 9th solution with dichloromethane extraction, get organic phase anhydrous sodium sulfate drying, after filtering, removing methylene dichloride obtains oily crude product, take volume ratio as the ethyl acetate of 1:40 ~ 1:60 and the mixed solution of ether be eluent, by described oily crude product purified by silica gel chromatographic column separating-purifying, obtain described compd E.

10. the synthetic method of natural product Pachycladin D as claimed in claim 7, it is characterized in that, described (1S, 2S)-pseudoephenamine is prepared by following steps:

Compound 1:

Compound 2:

Compound 3:

Compound 4:

(1S,2S)-pseudoephenamine：