CN108329375A - The preparation method of steroidal compounds - Google Patents

The preparation method of steroidal compounds Download PDF

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CN108329375A
CN108329375A CN201810205745.XA CN201810205745A CN108329375A CN 108329375 A CN108329375 A CN 108329375A CN 201810205745 A CN201810205745 A CN 201810205745A CN 108329375 A CN108329375 A CN 108329375A
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CN108329375B (en
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刘君羊
吴建磊
范建红
李闯创
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Southwest University of Science and Technology
Southern University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J67/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of two rings, each by one atom

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Abstract

The present invention relates to a kind of preparation methods of steroidal compounds.The preparation method of the steroidal compounds is by using structural formulaCompound A be starting material, by by type II [5+2] reaction be used as key reaction, efficiently, rapidly construct containing end of the bridge double bond, hightension [4,4,1] bicyclic skeleton, utilize lithium ethamine condition cut-out C=O bond；It goes formolation to obtain ketone in aerobic conditions oxidation using potassium tert-butoxide, finally lithium reagent addition is utilized to introduce side chain, to which steroidal compounds cyclocitrinol be prepared, i.e., structural formula is prepared by chemically synthesized method is

Description

The preparation method of steroidal compounds
Technical field
The present invention relates to a kind of preparation methods of steroidal compounds.
Background technology
Cyclocitrinol was divided from sponge penicillium citrinum by Kozlovsky et al. in 2000 It is a kind of novel steroidal compounds from a kind of natural products that class obtains.Its correct structure is by Philip Crews groups In the X-ray single crystal diffraction structure prediction by its family's analog in 2003.Up to the present more than 20 families are shared Race's natural products is isolated and identified out.Cyclocitrinols families natural products all has unique chemical constitution special Point：With the common Fourth Ring [7-7-6-5] core skeleton, wherein A/B ring systems are larger bicyclic [4.4.1] the bridged ring body of tension System；There are an end of the bridge double bond in A rings, there is great ring strain, be it is fully synthetic in a major challenge.Meanwhile Multiple compounds in cyclocitrinol families natural products show special bioactivity, to GPR12Chinese hamster ovary celI Test shows that multiple compounds in this family can stimulate cAMP (cyclic adenosine in low concentration Monophosphate generation), and this activity is receptor-independent, and these results help to understand nerve cell again Life system and the therapy for exploring nerve damage associated disease, in addition, they also show staphylococcus epidermis and enterococcus Go out weak resistance.Since the unique structures of cyclocitrinol and significant physiological activity are shown as drug leads chemical combination Therefore the potentiality of object synthesize this kind of natural products and are of great significance.However, so far without the complete of this kind of natural products Synthesis report.
Invention content
Based on this, it is necessary to a kind of preparation method of steroidal compounds is provided, to be prepared by chemical combination synthetic method To steroidal compounds cyclocitrinol, in order to increase the source of steroidal compounds cyclocitrinol.
A kind of preparation method of steroidal compounds, includes the following steps：
Anhydrous and under conditions of -78 DEG C, it is by structural formulaCompound A and diisopropylaminoethyl Lithium reacts 0.5 hour~4 hours in the first organic solvent, and trim,ethylchlorosilane is then added, and the reaction was continued, obtains containing knot Structure formula isCompound B the first crude product, wherein the compound A and the diisopropyl ammonia The molar ratio of base lithium is 1:1~1:The molar ratio of 2.5, the compound A and the trim,ethylchlorosilane is 1:1~1:2, Me are Methyl, TMS are trimethyl silicon substrate；
At room temperature, first crude product is reacted in a second organic solvent with 2- iodosobenzoic acids, is tied Structure formula isCompound C, wherein the molar ratio of the compound A and the 2- iodosobenzoic acids is 1:1~1:2.5；
It is anhydrous and under conditions of 0 DEG C, the compound C and azidotrimethylsilane is anti-in third organic solvent It answers 1 hour~5 hours, iodine and pyridine is then added, and the reaction was continued at room temperature 10 hours~14 hours, obtaining structural formula isCompound D, wherein the molar ratio of the compound C and the azidotrimethylsilane is 1:1 ~1:The molar ratio of 5, the compound C and the pyridine is 1:5~1:10, the molar ratio of the compound C and the iodine is 1:1~1:5；
In room temperature and the atmosphere of protective gas, cuprous, lithium acetate, catalyst by the compound D and thiophene -2-carboxylic acid It is with structural formulaCompound E reacted 8 hours~10 hours in the 4th organic solvent, tied Structure formula isCompound F, wherein the compound D and the thiophene -2-carboxylic acid are sub- The molar ratio of copper is 1:1~1:The molar ratio of 1.5, the compound D and the lithium acetate is 1:2~1:4, the compound D Molar ratio with the compound E is 1:1~1:2, TBS be t-Butyldimethylsilyl,nBu is normal-butyl；
The compound F, Nickel Chloride and sodium borohydride are mixed in the 5th organic solvent at -78 DEG C, until anti- System is answered to be warming up to room temperature from -78 DEG C, obtaining structural formula isCompound G, wherein The molar ratio of the compound F and the Nickel Chloride is 1:3~1:8, the molar ratio of the compound F and the sodium borohydride It is 1:5~1:15；
Anhydrous and under conditions of -78 DEG C, it is by structural formulaCompound H, tert-butyl lithium is the 6th It is reacted 0.5 hour~1 hour in organic solvent, the compound G is then added, and the reaction was continued, and obtaining structural formula isCompound I, wherein the molar ratio of the compound G and the compound H are 1: 2~1:The molar ratio of 4, the compound G and the tert-butyl lithium is 1:3~1:6, TIPS be triisopropylsilyl；
At room temperature, that the compound I in the 7th organic solvent is reacted 0.5 hour~2 with tetrabutyl ammonium fluoride is small When, sodium acetate, sodium bicarbonate and N- bromo-succinimides are then added under conditions of 0 DEG C, and reacted under conditions of 0 DEG C 0.5 hour~1 hour, obtain be containing structural formulaCompound J the second crude product, In, the molar ratio of the compound I and the tetrabutyl ammonium fluoride is 1:2.5~1:4, the compound I and the sodium acetate Molar ratio be 1:1~1:The molar ratio of 3, the compound I and the sodium bicarbonate is 1:1~1:3, the compound I with The molar ratio of the N- bromo-succinimides is 1:1~1:2；
Anhydrous and at room temperature, by second crude product, 4-dimethylaminopyridine, 2,2,6,6- tetramethyl piperidines and vinegar Acid anhydrides reacts in the 8th organic solvent, obtain be containing structural formulaCompound K Three crude products, wherein the molar ratio of the compound I and the 4-dimethylaminopyridine is 1:0.1~1:1, the compound I Molar ratio with the 2,2,6,6- tetramethyl piperidines is 1:2~1:4, the molar ratio of the compound I and the acetic anhydride Example is 1:2~1:4, Ac be acetyl group；
In anhydrous conditions, by the third crude product and 2,2,6,6- tetramethyl piperidines in the 9th organic solvent in It is reacted at 145 DEG C~160 DEG C, obtaining structural formula isCompound L, wherein the chemical combination The molar ratio of object I and the 2,2,6,6- tetramethyl piperidines is 1:1.5~1:4；
Under conditions of 0 DEG C, the compound L is reacted with sodium borohydride in the mixed liquor of tetrahydrofuran and water, is obtained It is to containing structural formulaCompound M the 4th crude product, wherein the compound L with The molar ratio of the sodium borohydride is 1:1~1:3；
Anhydrous and under conditions of -78 DEG C, will the 4th crude product with bis- (trimethylsilyl) potassamides the tenth It is reacted in organic solvent 0.1 hour~1 hour, carbon disulfide and iodomethane is then added, the reaction was continued 1 hour~2 hours, obtains It is to containing structural formulaCompound N the 5th crude product, wherein the compound L Molar ratio with bis- (trimethylsilyl) potassamides is 1:1~1:1.5, the compound L and the carbon disulfide Molar ratio is 1:2~1:8, the molar ratio of the compound L and the iodomethane is 1:2~1:8；
Under 80 DEG C~110 DEG C atmosphere with protective gas, by the 5th crude product, azodiisobutyronitrile and three positive fourths Ji Xiization hydrogen reacts in the 11st organic solvent, obtains structural formula and isCompound O, wherein The molar ratio of the compound L and the azodiisobutyronitrile is 1:0.1~1:0.4, the compound L and three normal-butyl The molar ratio of tin hydrogen is 1:4~1:10；
Under conditions of 0 DEG C, the compound O, 2,4,6- trimethylpyridines, thionyl chloride and pyridine are had the 12nd Reacted in solvent, obtain be containing structural formulaCompound P the 6th crude product, wherein institute The molar ratio for stating compound O and the 2,4,6- trimethylpyridines is 1:5~1:10, the compound O and the thionyl chloride Molar ratio be 1:2~1:The molar ratio of 5, the compound O and the pyridine is 1:4~1:6；
Anhydrous and at room temperature, the 6th crude product and lithium are reacted in ethamine, obtaining structural formula isCompound Q, wherein the molar ratio of the compound O and the lithium is 1:5~1:20；
At room temperature, by the compound Q, tetrabutylammonium chloride, 2,2,6,6- tetramethyl piperidine oxides and N- chloros Succimide reacts in the mixed solution of the 13rd organic solvent and carbonate buffer solution, obtains structural formula and isCompound R, wherein the molar ratio of the compound Q and the tetrabutylammonium chloride is 1:2 ~1:5, the molar ratio of the compound Q and described 2,2,6,6- tetramethyl piperidine oxides is 1:0.2~1:1, the chemical combination The molar ratio of object Q and the N- chlorosuccinimides is 1:2~1:8；
Anhydrous and under conditions of -78 DEG C, by the compound R, 2,6- lutidines and triethyl group silicon substrate fluoroform Sulphonic acid ester reacts in the 14th organic solvent, obtains structural formula and isCompound S, wherein The molar ratio of the compound R and the 2,6- lutidines is 1:3~1:6, the compound R and the triethyl group silicon substrate The molar ratio of triflate is 1:2~1:4, TES be triethyl group silicon substrate；
At room temperature, the compound S and potassium tert-butoxide are carried out in the 15th organic solvent under anhydrous and oxygen-free environment Hydrogen reaction is pulled out, is then reacted 0.1 hour~0.3 hour under aerobic environment, obtaining structural formula is Compound T, wherein the molar ratio of the compound S and the potassium tert-butoxide is 1:2~1:5；
Anhydrous and under conditions of -78 DEG C, it is by structural formulaCompound U and n-BuLi the tenth It is reacted 0.5 hour~1 hour in six organic solvents, the compound T is then added, the reaction was continued 0.1 hour~1 hour, then Reaction is quenched with methanol, obtains reaction solution, then at room temperature, tetrabutyl ammonium fluoride is added in the reaction solution, and react 1 Hour~2 hours, obtaining structural formula isSteroidal compounds, wherein the compound The molar ratio of the T and compound U is 1:4~1:The molar ratio of 8, the compound T and the n-BuLi is 1:3~1:6, The molar ratio of the compound T and the tetrabutyl ammonium fluoride is 1:12~1:20, X are selected fromnBu3One kind in Sn and I.
The preparation method of above-mentioned steroidal compounds is used as key reaction by type II [5+2] reactions, efficiently, rapidly Containing end of the bridge double bond, hightension [4,4,1] bicyclic skeleton is constructed, C=O bond is cut off using the condition of lithium-ethamine；Profit It goes formolation to obtain ketone in aerobic conditions oxidation with potassium tert-butoxide, finally lithium reagent addition is utilized to introduce side chain, to be prepared into To steroidal compounds cyclocitrinol, i.e., steroidal compounds are prepared by chemically synthesized method Cyclocitrinol, to increase the source of steroidal compounds cyclocitrinol, in order to study and use.
Specific implementation mode
To facilitate the understanding of the present invention, below to invention is more fully described.Following present the present invention compared with Good embodiment.But the present invention can realize in many different forms, however it is not limited to embodiment described herein. It is made the disclosure of the present invention more thorough and comprehensive on the contrary, purpose of providing these embodiments is.
Unless otherwise defined, all of technologies and scientific terms used here by the article and belong to the technical field of the present invention The normally understood meaning of technical staff is identical.Used term is intended merely to description tool in the description of the invention herein The purpose of the embodiment of body, it is not intended that in the limitation present invention.Term " and or " used herein includes one or more phases Any and all combinations of the Listed Items of pass.
The preparation method of the steroidal compounds of one embodiment is used to prepare steroidal compounds cyclocitrinol, the party Method includes the following steps：
Step S110：Anhydrous and under conditions of -78 DEG C, it is by structural formulaCompound A and two it is different Propylcarbamic lithium reacts 0.5 hour~4 hours in the first organic solvent, and trim,ethylchlorosilane is then added, and the reaction was continued, obtains It is to containing structural formulaCompound B the first crude product.
Wherein, the molar ratio of compound A and lithium diisopropylamine is 1:1~1:2.5, compound A and trimethylchloro-silicane The molar ratio of alkane is 1:1~1:2, Me be methyl, and TMS is trimethyl silicon substrate.
Specifically, it is added in trim,ethylchlorosilane the reaction was continued step, it is whether complete using thin-layered chromatography detection reaction. It is 1 hour~4 hours that the trim,ethylchlorosilane time that the reaction was continued, which is added,.First organic solvent is anhydrous tetrahydro furan or anhydrous Ether.
Specifically, in step s 110, after waiting for that the reaction was complete, after reaction is quenched with saturated ammonium chloride solution, ether is used Dilution, extraction reaction solution, water phase are extracted with ether, and organic phase uses saturated ammonium chloride and saturated common salt water washing successively.After washing Organic phase anhydrous sodium sulfate dry filter, be spin-dried for organic solvent under decompression, obtained liquid is quickly eluted with silicagel column, is obtained To the first crude product.Wherein, it is 1 that eluent, which is volume ratio,:10:0.01 ethyl acetate, n-hexane and triethylamine.
Step S120：At room temperature, the first crude product is reacted in a second organic solvent with 2- iodosobenzoic acids, is obtained It is to structural formulaCompound C.
The molar ratio of compound A and 2- iodosobenzoic acids is 1:1~1:2.5.Herein, signified room temperature is 20 DEG C ~30 DEG C.
Specifically, the second organic solvent is dimethyl sulfoxide or n,N-Dimethylformamide.
Specifically, it in the step of the first crude product being reacted in a second organic solvent with 2- iodosobenzoic acids, uses Thin-layered chromatography detection is until the first crude product disappears, i.e., the reaction was complete.By the first crude product and 2- iodosobenzoic acids the The time reacted in two organic solvents is 1 hour~5 hours.
Specifically, the first crude product of step S120 and 2- iodosobenzoic acids are obtained by the reaction in a second organic solvent Reaction solution is diluted with ether, is extracted, organic phase saturated common salt water washing, and the organic phase after washing is dry with anhydrous sodium sulfate solid Organic solvent, then is spin-dried for by filtering under reduced pressure after dry, and gained liquid silica gel column chromatography detaches to get to the compound of purifying C。
Step S130：It is anhydrous and under conditions of 0 DEG C, compound C is organic molten in third with azidotrimethylsilane It is reacted in agent 1 hour~5 hours, iodine and pyridine is then added, and the reaction was continued at room temperature 10 hours~14 hours, is tied Structure formula isCompound D.
Wherein, the molar ratio of compound C and azidotrimethylsilane is 1:1~1:5, mole of compound C and pyridine Than being 1:5~1:The molar ratio of 10, compound C and iodine is 1:1~1:5.
In the present embodiment, step S130 is specially：In anhydrous conditions, that compound C is dissolved in third is organic molten In agent, the third organic solution of compound C is obtained；Iodine is dissolved in pyridine, the pyridine solution of iodine is obtained；In 0 DEG C of condition Under, azidotrimethylsilane is added in the third organic solution of compound C, reacts 1 hour~5 hours, iodine is then added Pyridine solution, be then warming up to room temperature, the reaction was continued 10 hours~14 hours.The so operation of this step is conducive to improve chemical combination The yield of object D.
Specifically, third organic solvent is anhydrous methylene chloride or chloroform.
Specifically, iodine and pyridine is added, and the step of the reaction was continued at room temperature 10 hours~14 hours is after the meeting：It will reaction System is down to 0 DEG C, saturated sodium thiosulfate is added, reaction is quenched, and with ether dilution, extraction reaction system, organic phase is successively with full And organic solvent after anhydrous sodium sulfate solid dry filter, is spin-dried for, gained by ammonium chloride, saturated common salt water washing under reduced pressure Liquid silica gel column chromatography, the compound D purified.
Step S140：In room temperature and the atmosphere of protective gas, by compound D and thiophene -2-carboxylic acid cuprous (CuTC), vinegar Sour lithium, catalyst and structural formula areCompound E reacted in the 4th organic solvent, obtain structural formula ForCompound F.
Compound D is 1 with the cuprous molar ratio of thiophene -2-carboxylic acid:1~1:1.5, the molar ratio of compound D and lithium acetate It is 1:2~1:The molar ratio of 4, compound D and compound E are 1:1~1:2, TBS be t-Butyldimethylsilyl,nBu is positive fourth Base.
Specifically, catalyst is tetra-triphenylphosphine palladium.More specifically, the molar ratio of compound D and catalyst is 1:0.01 ~1:0.05.
Specifically, the 4th organic solvent is N-methyl pyrrolidones or tetrahydrofuran.Protective gas is nitrogen or argon gas.
Specifically, when compound D is cuprous with thiophene -2-carboxylic acid, lithium acetate, tetra-triphenylphosphine palladium and compound E react Between be 8 hours~10 hours.In step S140, compound D and thiophene -2-carboxylic acid is cuprous, lithium acetate, tetra-triphenylphosphine palladium and The reaction solution that compound E is obtained after being reacted in the 4th organic solvent 8 hours~10 hours is diluted with ether, is extracted, organic Saturated common salt water washing, then anhydrous sodium sulfate solid dry filter are mutually used, is under reduced pressure spin-dried for organic solvent, gained liquid is used After silica gel column chromatography, the compound F that is purified.
Step S150：Compound F, Nickel Chloride and sodium borohydride are mixed in the 5th organic solvent at -78 DEG C, directly It is warming up to room temperature to reaction system from -78 DEG C, obtaining structural formula isCompound G.
Wherein, the molar ratio of compound F and Nickel Chloride is 1:3~1:The molar ratio of 8, compound F and sodium borohydride is 1:5~1:15.Nickel Chloride is added by way of six hydration Nickel Chlorides, can also be directly added into pure Nickel Chloride.
Specifically, the 5th organic solvent be methanol or be first alcohol and water mixed solution.
Specifically, in step S150, reaction system is warming up to after room temperature, with ethyl acetate diluting reaction system, then Diatomite is added, the mother liquor for filtering gained is washed with saturated ammonium chloride solution, saturated common salt aqueous solution successively, and anhydrous sodium sulfate is dry It is dry, after filter, organic solvent is spin-dried under reduced pressure, obtained liquid silica gel column chromatography obtains chemical combination after purification Object G.
Step S160：Anhydrous and under conditions of -78 DEG C, it is by structural formulaCompound H, tertiary butyl Lithium reacts 0.5 hour~1 hour in the 6th organic solvent, and compound G is then added, and the reaction was continued, and obtaining structural formula isCompound I.
The molar ratio of compound G and compound H is 1:2~1:The molar ratio of 4, compound G and tert-butyl lithium is 1:3~1: 6, TIPS be triisopropylsilyl.
In the present embodiment, the 6th organic solvent is made of anhydrous ether and anhydrous pentane；At this point, step S160 tools Body is：Under conditions of -78 DEG C, compound H is dissolved in anhydrous ether, forms the diethyl ether solution of compound H；By tertiary butyl The pentane solution of lithium, which is added in the diethyl ether solution of compound H, to react 0.5 hour~1 hour, and the anhydrous of compound G is then added Diethyl ether solution, the reaction was continued.So operation is conducive to that compound I is made to have higher yield.
It is made of anhydrous ether and anhydrous pentane it should be noted that the 6th organic solvent is also unlimited, the 6th is organic molten Agent can also be anhydrous tetrahydro furan or anhydrous pentane.
Specifically, it is 1 hour~2 hours that the compound G times that the reaction was continued, which are added,.
Specifically, it in step S160, is quenched instead with saturated ammonium chloride solution after the step of being added compound G the reaction was continued It answers, with ether dilute reaction solution, combined organic phase uses saturated ammonium chloride and saturated common salt water washing successively, and organic phase is with anhydrous After sodium sulphate dry filter, organic solvent is spin-dried under reduced pressure, obtained liquid silica gel column chromatography, the chemical combination purified Object I.
Step S170：At room temperature, compound I is reacted 0.5 hour with tetrabutyl ammonium fluoride in the 7th organic solvent ~2 hours, water, sodium acetate, sodium bicarbonate and N- bromo-succinimides are then added under conditions of 0 DEG C, and in 0 DEG C of item Reacted 0.5 hour~1 hour under part, obtain be containing structural formulaCompound J it is second thick Product.
The molar ratio of compound I and tetrabutyl ammonium fluoride is 1:2.5~1:The molar ratio of 4, compound I and sodium acetate is 1: 1~1:The molar ratio of 3, compound I and sodium bicarbonate is 1:1~1:3, the molar ratio of compound I and N- bromo-succinimides It is 1:1~1:2.
Specifically, the 7th organic solvent be tetrahydrofuran or be tetrahydrofuran and water mixed solution.
Specifically, in step S170, water, sodium acetate, sodium bicarbonate and N- bromo-succinimides is added, and at 0 DEG C Under the conditions of react 0.5 hour~1 hour after with saturated sodium thiosulfate solution reaction is quenched, with ethyl acetate dilution, extraction, have Machine mutually uses saturated ammonium chloride solution, the washing of saturated common salt aqueous solution to be dried with anhydrous sodium sulfate solid successively, and filtering is being depressurized It is lower that organic solvent is spin-dried for get to the second crude product containing compound J.
Step S180：Anhydrous and at room temperature, by the second crude product, 4-dimethylaminopyridine, 2,2,6,6- tetramethyl piperazines Pyridine and acetic anhydride react in the 8th organic solvent, obtain be containing structural formulaCompound K Third crude product.
Wherein, the molar ratio of compound I and 4-dimethylaminopyridine is 1:0.1~1:1, compound I and described 2,2,6, The molar ratio of 6- tetramethyl piperidines is 1:2~1:The molar ratio of 4, compound I and acetic anhydride is 1:2~1:4, Ac be acetyl Base.
Specifically, the 8th organic solvent is anhydrous methylene chloride or anhydrous acetonitrile.
Specifically, in step S180, the second crude product, 4-dimethylaminopyridine, 2,2,6,6- tetramethyl piperidines and acetic acid Acid anhydride reaction solution obtained by the reaction in the 8th organic solvent is filtered with short column of silica gel, filtrate be spin-dried under reduced pressure concentration to get to Third crude product.Second crude product, 4-dimethylaminopyridine, 2,2,6,6- tetramethyl piperidines and acetic anhydride are in the 8th organic solvent The time of middle reaction is 0.5 hour~1 hour.
Step S190：In anhydrous conditions, by third crude product and 2,2,6,6- tetramethyl piperidines are in the 9th organic solvent In reacted at 145 DEG C~160 DEG C, obtaining structural formula isCompound L.
Wherein, the molar ratio of compound I and 2,2,6,6- tetramethyl piperidines are 1:1.5~1:4.Specifically, the 9th is organic Solvent is anhydrous acetonitrile, dry toluene or anhydrous methylene chloride etc..In step S190, third crude product and 2,2,6,6- tetramethyls The time that piperidines reacts in the 9th organic solvent at 145 DEG C~160 DEG C is 10 hours~12 hours.
Further, third crude product and 2,2,6,6- tetramethyl piperidines are in the 9th organic solvent in 145 DEG C~160 DEG C Under reaction solution obtained by the reaction cooling, organic solvent is spin-dried under reduced pressure, gained liquid silica gel column chromatography is purified Compound L.
Step S210：It is under conditions of 0 DEG C, compound L and sodium borohydride is anti-in the mixed liquor of tetrahydrofuran and water Answer, obtain be containing structural formulaCompound M the 4th crude product.
Wherein, the molar ratio of compound L and sodium borohydride is 1:1~1:3.
Specifically, in the mixed liquor of tetrahydrofuran and water, the volume ratio of tetrahydrofuran and water is 2:1~6:1.
Specifically, the time that compound L and sodium borohydride react in the mixed liquor of tetrahydrofuran and water is 0.5 hour~ 2 hours.
Further, compound L uses saturated ammonium chloride after being reacted in the mixed liquor of tetrahydrofuran and water with sodium borohydride Reaction is quenched in solution, and with ethyl acetate dilution, extraction, organic phase uses saturated ammonium chloride solution, saturated common salt aqueous solution to wash successively It washs, is dried with anhydrous sodium sulfate solid, organic solvent is spin-dried for, obtains the 4th crude product M by filtering under reduced pressure.
Step S220：Anhydrous and under conditions of -78 DEG C, the 4th crude product and bis- (trimethylsilyl) potassamides are existed It reacts 0.1 hour~1 hour in tenth organic solvent, carbon disulfide and iodomethane is then added, it is 1 hour~2 small that the reaction was continued When, obtain be containing structural formulaCompound N the 5th crude product.
Wherein, the molar ratio of compound L and bis- (trimethylsilyl) potassamides is 1:1~1:1.5, compound L and two The molar ratio of nitric sulfid is 1:2~1:8, the molar ratio of compound L and iodomethane is 1:2~1:8.
Specifically, the tenth organic solvent is anhydrous tetrahydro furan or anhydrous ether.
Specifically, carbon disulfide is added and iodomethane is quenched after the reaction was continued 1 hour~2 hours with saturated ammonium chloride solution It goes out, with ethyl acetate dilution, extraction, organic phase uses saturated ammonium chloride solution, saturated common salt aqueous solution washing, with anhydrous sulphur successively Sour sodium solid drying, filtering.Organic solvent is spin-dried under reduced pressure.
Step S230：Under the atmosphere of 80 DEG C~110 DEG C and protective gas, by the 5th crude product, azodiisobutyronitrile with Tri-n-butyl tin hydrogen reacts in the 11st organic solvent, obtains structural formula and isCompound O。
Wherein, the molar ratio of compound L and azodiisobutyronitrile is 1:0.1~1:0.4, compound L and tri-n-butyl tin The molar ratio for changing hydrogen is 1:4~1:10.
Specifically, the 11st organic solvent is dry toluene or anhydrous benzene.Protective gas is argon gas or nitrogen.It is thick by the 5th Product, azodiisobutyronitrile and the time that tri-n-butyl tin hydrogen reacts in the 11st organic solvent are 1 hour~2 hours.
Specifically, in step S230, the 5th crude product, azodiisobutyronitrile and tri-n-butyl tin hydrogen are had the 11st Reaction solution after being reacted in solvent is cooled to room temperature, then after reaction solution is spin-dried for concentration, and gained liquid is detached with silica gel column chromatography Purifying, the compound O purified.
Step S240：Under conditions of 0 DEG C, by compound O, 2,4,6- trimethylpyridines, thionyl chloride and pyridine are Reacted in 12 organic solvents, obtain be containing structural formulaCompound P the 6th crude product.
Wherein, the molar ratio of compound O and 2,4,6- trimethylpyridines are 1:5~1:10, compound O and thionyl chloride Molar ratio is 1:2~1:The molar ratio of 5, compound O and pyridine is 1:4~1:6.
Specifically, the 12nd organic solvent is anhydrous methylene chloride or anhydrous 1,2- dichloroethanes.Compound O, 2,4,6- The time that trimethylpyridine, thionyl chloride and pyridine react in the 12nd organic solvent is 0.2 hour~0.5 hour.
Further, compound O, 2,4,6- trimethylpyridines, thionyl chloride and pyridine are anti-in the 12nd organic solvent Should after reaction is quenched with saturated sodium bicarbonate solution after, with ether dilution, extraction, organic phase successively use hydrochloric acid, saturated salt solution It is dried, is filtered with anhydrous sodium sulfate after washing.After organic solvent is spin-dried under reduced pressure, the 6th crude product is obtained.Wherein, the 6th Crude product is the mixture that three-level hydroxyl eliminates product P, P' and P "；Wherein, P:P':P "=9:1:1.The structural formula of P' and P " point It is not as follows：
Step S250：Anhydrous and at room temperature, the 6th crude product and lithium are reacted in ethamine, obtaining structural formula isCompound Q.
Wherein, the molar ratio of compound O and lithium is 1:5~1:20.
In the present embodiment, the step of the 6th crude product and lithium being reacted in anhydrous ethylamine be specially：In the item of room temperature Under part, the 6th crude product is dissolved in anhydrous ethylamine, lithium is then added, after reacting 0.5 hour~1 hour, is cooled to -78 DEG C, reaction is quenched with isoprene and saturated ammonium chloride solution successively.
Specifically, after reaction being quenched with isoprene and saturated ammonium chloride solution, ether dilution, extraction, organic phase is added It uses saturated ammonium chloride solution, the washing of saturated common salt aqueous solution to be dried with anhydrous sodium sulfate solid, filtering successively, under reduced pressure will Organic solvent is spin-dried for, gained liquid silica gel column chromatography separating purification, the compound Q purified.
Step S260：At room temperature, by compound Q, tetrabutylammonium chloride, 2,2,6,6- tetramethyl piperidine oxides and N- Chlorosuccinimide reacts in the mixed solution of the 13rd organic solvent and carbonate buffer solution, obtains structural formula and isCompound R.
Wherein, compound and the molar ratio of tetrabutylammonium chloride are 1:2~1:5, compound Q and 2,2,6,6- tetramethyl piperazines The molar ratio of pyridine oxide is 1:0.2~1:1.0, the molar ratio of compound Q and N- chlorosuccinimides is 1:2~1:8.
Specifically, the 13rd organic solvent is dichloromethane.Carbonate buffer solution is the mixing of sodium bicarbonate and potassium carbonate Aqueous solution.Wherein, in the buffer solution of carbonate, the molar concentration of sodium bicarbonate is 0.5mol/L, the molar concentration of potassium carbonate For 0.05mol/L.The pH value of carbonate buffer solution is 8.6.
Specifically, by compound Q, tetrabutylammonium chloride, 2,2,6,6- tetramethyl piperidine oxides and N- chloro succinyl In the step of imines reacts in the mixed solution of the 13rd organic solvent and carbonate buffer solution, detected with thin-layered chromatography anti- Should whether completely.
Specifically, by compound Q, tetrabutylammonium chloride, 2,2,6,6- tetramethyl piperidine oxides and N- chloro succinyl Imines in the mixed solution of the 13rd organic solvent and carbonate buffer solution reaction solution obtained by the reaction with ethyl acetate dilute, Extraction, organic phase use saturated sodium thiosulfate, saturated common salt water washing to be dried with anhydrous sodium sulfate successively, and organic phase decompression is dense After contracting, residue silica gel post separation, the compound R purified.
Step S270：Anhydrous and under conditions of -78 DEG C, by compound R, 2,6- lutidines and triethyl group silicon substrate three Fluorine methanesulfonates reacts in the 14th organic solvent, obtains structural formula and isCompound S.
Wherein, the molar ratio of compound R and 2,6- lutidines is 1:3~1:6, compound R and triethyl group silicon substrate three The molar ratio of fluorine methanesulfonates is 1:2~1:4, TES be triethyl group silicon substrate.
Specifically, the 14th organic solvent is anhydrous methylene chloride or anhydrous 1,2- dichloroethanes.
Specifically, compound R, 2,6- lutidines and triethyl group silicon substrate triflate are in the 14th organic solvent After middle reaction 0.5 hour~1 hour, saturated sodium bicarbonate solution is added, reaction is quenched, is reacted with ethyl acetate dilution, extraction Liquid, organic phase are dried after saturated common salt water washing with anhydrous sodium sulfate, filtering, after organic phase is concentrated under reduced pressure, residue silica gel Column chromatographic isolation and purification, the compound S purified.
Step S280：At room temperature, by compound S and potassium tert-butoxide in the 15th organic solvent under anhydrous and oxygen-free environment into Row pulls out hydrogen reaction, is then reacted 0.1 hour~0.3 hour under aerobic environment, obtaining structural formula is Compound T.
Wherein, the molar ratio of compound S and potassium tert-butoxide is 1:2~1:5.
In the present embodiment, the 15th organic solvent is made of anhydrous tertiary butanol and anhydrous tetrahydro furan.At this point, in room Under temperature, the step of compound S and potassium tert-butoxide are carried out pulling out hydrogen reaction in the 15th organic solvent under anhydrous and oxygen-free environment Specially：At room temperature, compound S is dissolved in anhydrous tertiary butanol, obtains the anhydrous tertiary butanol solution of compound S；Then In the absence of oxygen, the anhydrous tetrahydrofuran solution that potassium tert-butoxide is added in the anhydrous tertiary butanol solution of compound S carries out Pull out hydrogen reaction.The operation is conducive to improve the yield of compound T.
It should be noted that the 15th organic solvent is not limited to be made of anhydrous tertiary butanol and anhydrous tetrahydro furan, the tenth Five organic solvents can also be anhydrous tertiary butanol or anhydrous tetrahydro furan；If the 15th organic solvent is anhydrous tertiary butanol, changing The anhydrous tertiary butanol solution for closing addition potassium tert-butoxide in the anhydrous tertiary butanol solution of object S carries out pulling out hydrogen reaction；If the 15th is organic Solvent is anhydrous tetrahydro furan, and compound S is dissolved in anhydrous tetrahydro furan, and the anhydrous tetrahydro furan for obtaining compound S is molten Liquid；Then in the absence of oxygen, the anhydrous tetrahydro furan of potassium tert-butoxide is added in the anhydrous tetrahydrofuran solution of compound S Solution carries out pulling out hydrogen reaction.
Specifically, in step S280, after being reacted 0.1 hour~0.3 hour under aerobic environment, saturated ammonium chloride solution is used Reaction is quenched, reaction solution is extracted with ethyl acetate, organic phase is dried after saturated common salt water washing with anhydrous sodium sulfate, filtering, After organic phase is concentrated under reduced pressure, residue silica gel column chromatography separating purification, the compound T purified.
Step S290：Anhydrous and under conditions of -78 DEG C, it is by structural formulaCompound U and positive fourth Base lithium reacts 0.5 hour~1 hour in the 16th organic solvent, and compound T is then added, and it is 0.1 hour~1 small that the reaction was continued When, reaction is quenched in again with methanol, obtains reaction solution, then at room temperature, tetrabutyl ammonium fluoride is added in reaction solution, and react 1 hour~2 hours, obtaining structural formula wasSteroidal compounds.
Wherein, the molar ratio of compound T and compound U is 1:4~1:The molar ratio of 8, compound T and n-BuLi is 1: 3~1:The molar ratio of 6, compound T and tetrabutyl ammonium fluoride is 1:12~1:20, X are selected fromnBu3One kind in Sn and I.
Specifically, the molar ratio of compound T and methanol is 1:10~1:100.
In the present embodiment, the 16th organic solvent is made of anhydrous tetrahydro furan and anhydrous n-hexane.At this point, in nothing Under conditions of water and -78 DEG C, compound U and n-BuLi are reacted 0.5 hour~1 hour in the 16th organic solvent, so Compound T is added afterwards, the step of the reaction was continued 0.5 hour~1 hour is specially：Compound U is dissolved in anhydrous tetrahydro furan In, the anhydrous n-hexane solution of n-BuLi is then added under conditions of -78 DEG C, and 0.5 hour~1 is reacted at -78 DEG C Hour, it is subsequently added into the anhydrous tetrahydrofuran solution of compound T, the reaction was continued 0.5 hour~1 hour.This operation is conducive to carry The yield of high steroidal compounds.
It should be noted that the 16th organic solvent is not limited to be made of anhydrous tetrahydro furan and anhydrous n-hexane, for example, 16th organic solvent can also be anhydrous tetrahydro furan or anhydrous n-hexane.If the 16th organic solvent is anhydrous tetrahydrochysene furan It mutters, the anhydrous tetrahydrofuran solution of n-BuLi is added under conditions of -78 DEG C；If the 16th organic solvent be it is anhydrous just oneself Compound U is dissolved in anhydrous n-hexane by alkane, and compound T is added in a manner of the anhydrous n-hexane solution of compound T.
Specifically, tetrabutyl ammonium fluoride is added in the reaction solution, and uses saturation chlorination after reacting 1 hour~2 hours Reaction is quenched in ammonium salt solution, and ethyl acetate extracts reaction solution, and organic phase uses saturated ammonium chloride solution, saturated common salt aqueous solution to wash successively It washs, is dried with anhydrous sodium sulfate solid, organic solvent is spin-dried for, gained liquid silica gel column chromatography obtains by filtering under reduced pressure The steroidal compounds of purifying.
The preparation method of above-mentioned steroidal compounds is used as key reaction by type II [5+2] reactions, efficiently, rapidly Containing end of the bridge double bond, hightension [4,4,1] bicyclic skeleton is constructed, C=O bond is cut off using the condition of lithium-ethamine；Profit It goes formolation to obtain ketone in aerobic conditions oxidation with potassium tert-butoxide, finally lithium reagent addition is utilized to introduce side chain, to be prepared into To steroidal compounds cyclocitrinol, i.e., steroidal compounds are prepared by chemically synthesized method Cyclocitrinol, to increase the source of steroidal compounds cyclocitrinol, in order to study and use.This method operates Simply, respectively step yield is higher, is suitble to be widely popularized.
It is that (following embodiment unless otherwise specified, does not then contain and remove inevitable impurity specific embodiment part below Other components not yet explicitly pointed out in addition.)：
Embodiment 1
The step of preparation method of the steroidal compounds of the present embodiment, is as follows：
(1) at -78 DEG C, compound A (20.0g, 78.6mmol) is dissolved in anhydrous tetrahydro furan (300mL), is obtained To the tetrahydrofuran solution of compound A；At -78 DEG C, under continuous agitation, by the tetrahydrofuran solution of compound A It is added in lithium diisopropylamine (47.2mL, 2.0mol/L), and is stirred to react half an hour at such a temperature, front three is then added Base chlorosilane (7.5mL, 86.5mmol) continues to be stirred to react at such a temperature, is used in combination chromatographic sheet detection until having reacted Entirely, about 1 hour, reaction is quenched with saturated ammonium chloride solution, with ether dilution, extraction reaction solution, organic phase is successively with saturation chlorine Change ammonium and saturated common salt water washing, then with anhydrous sodium sulfate dry filter, is spin-dried for organic solvent under decompression, obtained liquid silicon (eluent is that volume ratio is 1 to glue short column:10:0.01 ethyl acetate, the mixture of n-hexane and triethylamine) quickly elution, it obtains To the first crude product containing compound B (silyl enol ether), about 26.0g.
(2) the first crude product of above-mentioned gained is dissolved in analytically pure dimethyl sulfoxide (DMSO) (100mL), at room temperature, is added Enter 2- iodosobenzoic acids (28.6g, 102.2mmol), continue to be stirred to react, chromatographic sheet detection is used in combination until the first thick production Object disappears, about 3 hours, then with ether dilution, extraction reaction solution, organic phase with saturated common salt water washing for several times, then will be organic It filtering after mutually being dried with anhydrous sodium sulfate solid, is under reduced pressure spin-dried for organic solvent, gained liquid is detached with silica gel column chromatography, Obtain compound C, about 15.8g, yield 80%.Wherein, the detection data of compound C is as follows：(c 0.93, CHCl3)；1H NMR (500MHz, CDCl3) δ 6.77 (ddd, J=9.7,5.8,2.1Hz, 1H), 6.00 (dd, J=10.1, 3.2Hz, 1H), 4.14 (d, J=2.4Hz, 1H), 3.46 (d, J=1.1Hz, 3H), 3.40 (d, J=1.1Hz, 3H), 2.68- 2.54 (m, 2H), 2.52-2.42 (m, 1H), 2.01-1.89 (m, 1H), 1.84-1.76 (m, 3H), 1.76-1.69 (m, 1H), 1.50-1.37 (m, 1H), 0.98 (d, J=6.5Hz, 3H), 0.76 (s, 3H)；13C NMR (125MHz, CDCl3) δ 201.8, 147.7,129.5,108.7,58.7,57.0,56.1,52.4,47.5,42.8,39.2,26.9,19.6,11.9,11.6.Chemical combination The synthetic route of object C is as follows：
(3) iodine (50.3g, 198.3mmol) is dissolved in pyridine (44.7mL, 555.0mmol), the pyridine for obtaining iodine is molten Liquid；Compound C (20.0g, 79.3mmol) is dissolved in anhydrous methylene chloride (300mL), azido three is added under the conditions of 0 DEG C Methyl-monosilane (36.5mL, 277.6mmol), and stir 2 hours at such a temperature, the pyridine of iodine is then slowly added dropwise at 0 DEG C Solution, reaction clear-cutting forestland are stirred overnight (about 10 hours) to the reaction was complete, reaction system are then down to 0 DEG C again to room temperature, Saturated sodium thiosulfate is added, reaction is quenched, with ether dilution, extraction reaction system, organic phase uses saturated ammonium chloride, satisfies successively And brine It, anhydrous sodium sulfate solid dry filter, then be under reduced pressure spin-dried for organic solvent, gained liquid silicagel column Chromatography, obtains compound D, about 21.0g, yield 70%.
The detection data of compound D is as follows：(c 1.00, CHCl3)；1H NMR (500MHz, CDCl3)δ 7.47 (dd, J=5.6,3.1Hz, 1H), 4.12 (d, J=2.6Hz, 1H), 3.44 (s, 3H), 3.39 (s, 3H), 2.71 (t, J= 9.6Hz, 1H), 2.64-2.52 (m, 2H), 2.00-1.91 (m, 1H), 1.88-1.78 (m, 3H), 1.75-1.66 (m, 1H), 1.50-1.40 (m, 1H), 0.95 (d, J=6.7Hz, 3H), 0.77 (s, 3H)；13C NMR (125MHz, CDCl3) δ 194.6, 155.9,108.5,102.7,58.2,56.9,56.1,52.1,47.7,46.2,39.0,27.1,20.6,12.2,11.6.Chemical combination The synthetic route of object D is as follows：
(4) at room temperature, compound D (8.40g, 22.2mmol) is dissolved in analytically pure N-methyl pyrrolidones (50mL) In, then sequentially added in the environment of nitrogen protection CuTC (4.23g, 22.2mmol), lithium acetate (4.39g, 66.6mmol), Tetra-triphenylphosphine palladium (770mg, 0.66mmol), compound E (16.7g, 33.3mmol), and reaction 8 hours is stirred at room temperature, Obtained reaction solution is diluted with ether, is extracted, and organic phase uses saturated common salt water washing 3 times, is dry with anhydrous sodium sulfate solid successively It is dry, it then filters, then be under reduced pressure spin-dried for organic solvent, gained liquid is detached with silica gel column chromatography, obtains compound F, about 8.53g, yield 83%.
The detection data of compound F is as follows：(c 1.55, CHCl3)；1H NMR (500MHz, CDCl3)δ 7.96 (s, 1H), 6.83 (d, J=3.6Hz, 1H), 6.35 (s, 1H), 4.60 (s, 2H), 4.14 (s, 1H), 3.45 (s, 3H), 3.40 (s, 3H), 2.77-2.66 (m, 2H), 2.64-2.53 (m, 1H), 2.02-1.91 (m, 1H), 1.91-1.79 (m, 3H), 1.78-1.68 (m, 1H), 1.54-1.40 (m, 1H), 0.99 (d, J=6.7Hz, 3H), 0.90 (s, 9H), 0.79 (s, 3H), 0.08 (s, 6H)13C NMR (125MHz, CDCl3) δ 200.1,154.1,141.0,140.8,131.4,120.1,108.7, 105.4,59.1,58.2,57.0,56.1,52.5,47.7,42.9,39.1,27.2,25.9,19.8,18.4,12.1,11.6 ,- 5.2.The synthetic route of compound F is as follows：
(5) at room temperature, compound F (8.53g, 18.3mmol) is dissolved in the pure methanol (200mL) of analysis, adds six It is hydrated Nickel Chloride (25.0g, 91.5mmol), -78 DEG C is then cooled to, is carefully added into sodium borohydride (6.91g, 183mmol), And it is stirred to react at -78 DEG C until reaction system is slowly increased to room temperature, about 3 hours.Then ethyl acetate (500mL) is used to dilute Reaction system adds diatomite (30g), is filtered after stirring half an hour, mother liquid obtained to use saturated ammonium chloride solution, saturation successively Common salt aqueous solution washs, and organic solvent after filtering, is spin-dried for, obtained liquid silica gel by anhydrous sodium sulfate drying under reduced pressure Column chromatography obtains compound G, about 5.70g, yield 67%.
The detection data of compound G is as follows：(c 0.90, MeOH)；1H NMR (500MHz, CDCl3)δ7.33 (s, 1H), 6.18 (s, 1H), 4.62 (s, 2H), 4.16 (d, J=2.4Hz, 1H), 3.51-3.44 (m, 1H), 3.47 (s, 3H), 3.42 (s, 3H), 2.62 (dd, J=11.5,7.8Hz, 1H), 2.31 (dddd, J=13.7,6.8,4.5,2.3Hz, 1H), 2.18 (ddd, J=13.2,4.4,2.2Hz, 1H), 2.07-1.96 (m, 1H), 1.96-1.74 (m, 4H), 1.73-1.69 (m, 1H), 1.63-1.55 (m, 1H), 1.52-1.44 (m, 1H), 1.02 (d, J=6.5Hz, 3H), 0.92 (s, 9H), 0.71 (s, 3H), 0.10 (s, 6H)13C NMR (125MHz, CDCl3) δ 208.6,154.0,139.1,122.8,108.8,108.6,61.5, 58.3,57.0,56.1,52.6,50.9,47.6,39.2,39.1,32.7,27.3,25.9,19.4,18.5,12.5,11.8 ,- 5.2.The synthetic route of compound G is as follows：
(6) at -78 DEG C, compound H (3.20g, 9.90mmol) is dissolved in anhydrous ether (50mL), obtains compound The diethyl ether solution of H, then by the pentane solution (molar concentration 1.3mol/L) of the tert-butyl lithium of 11.42mL (14.85mmol) Be added in the diethyl ether solution of compound H, and half an hour be stirred to react at -78 DEG C, be subsequently added into compound G (2.3g, Anhydrous ether (20mL) solution 4.95mmol), continues to be stirred to react about 1 hour, then reaction is quenched with saturated ammonium chloride solution, With ether dilution, extraction reaction solution, after water phase is extracted 2 times with ether, organic phase merges, and saturated ammonium chloride and saturation is used to eat successively Salt water washing organic phase, then by organic phase anhydrous sodium sulfate dry filter, be under reduced pressure spin-dried for organic solvent, obtained liquid Body silica gel column chromatography obtains compound I, about 2.90g, yield 83%.
The detection data of compound I is as follows：(c 0.66, CHCl3)；1H NMR (500MHz, CDCl3)δ 7.23 (s, 1H), 6.25 (s, 1H), 5.65-5.54 (m, 1H), 5.13-4.97 (m, 2H), 4.59 (s, 2H), 4.15 (d, J= 2.4Hz, 1H), 3.50-3.44 (m, 1H), 3.46 (s, 3H), 3.39 (s, 3H), 3.34 (dd, J=9.4,7.9Hz, 1H), 2.61 (dd, J=12.8,4.2Hz, 1H), 2.33 (dt, J=8.6,4.1Hz, 1H), 2.05-1.91 (m, 2H), 1.90-1.79 (m, 1H), 1.76-1.68 (m, 2H), 1.65 (dd, J=14.0,3.1Hz, 1H), 1.58 (d, J=12.7Hz, 1H), 1.51-1.34 (m, 5H), 1.30-1.22 (m, 1H), 1.06-1.00 (m, 24H), 0.95 (d, J=6.7Hz, 3H), 0.90 (s, 9H), 0.07 (s, 3H), 0.07 (s, 3H)；13C NMR (125MHz, CDCl3) δ 153.4,141.5,139.8,126.7,116.1,109.9, 109.0,75.0,68.3,58.4,56.9,56.0,54.6,52.6,43.8,43.2,42.5,41.3,40.2,38.8,28.3, 27.0,25.9,20.6,18.5,18.0,13.2,11.9,11.5, -5.2.
The synthetic route of compound I is as follows：
(7) compound I (1.93g, 2.73mmol) is dissolved in analysis pure tetrahydrofuran (60mL), then in lasting stirring With the tetrahydrofuran solution (molar concentration for the tetrabutyl ammonium fluoride (6.90mmol) that 6.90mL under conditions of room temperature, is added 1.0mol/L), continue to stir half an hour to the reaction was complete, reaction system is then cooled to 0 DEG C, sequentially adds water (20mL), sodium acetate (0.76g, 6.03mmol), sodium bicarbonate (0.33g, 3.93mmol) and N- bromo-succinimides (0.56g, 3.14mmol), and reaction is to the reaction was complete at 0 DEG C, about half an hour, then be quenched with saturated sodium thiosulfate solution Reaction, with ethyl acetate dilution, extraction, organic phase uses saturated ammonium chloride solution, saturated common salt aqueous solution to wash successively, and use is anhydrous Solid sodium sulfate is dried, filtering.Organic solvent is spin-dried under reduced pressure, obtains the second crude product containing compound J.
(8) at room temperature, the second crude product is dissolved in anhydrous methylene chloride (50mL), sequentially adds 4- dimethylamino pyrroles Pyridine (0.16g, 1.36mmol), 2,2,6,6- tetramethyl piperidines (1.84mL, 10.9mmol), acetic anhydride (0.92mL, 8.19mmol), extremely the reaction was complete for reaction, about half an hour, and after reaction system short column of silica gel fast filtering, filtrate is revolved under reduced pressure Dry concentration, obtains the third crude product containing compound K.
(9) third crude product is dissolved in after anhydrous acetonitrile (750mL) and is transferred to 1L tube sealing bottles, 2,2,6,6- tetramethyls are added Piperidines (0.92mL, 5.45mmol).Be heated to 155 DEG C reaction 10 hours after, be cooled to room temperature, under reduced pressure revolve organic solvent Dry, gained liquid silica gel column chromatography obtains compound L, about 0.88g, yield 68%.
The detection data of compound L is as follows：(c 1.30, CHCl3)；1H NMR (500MHz, CDCl3)δ 6.23 (d, J=7.2Hz, 1H), 5.96 (s, 1H), 4.43 (d, J=8.3Hz, 1H), 4.11 (d, J=2.5Hz, 1H), 3.98 (dd, J=11.2,3.9Hz, 1H), 3.91 (dd, J=11.2,6.1Hz, 1H), 3.43 (s, 3H), 3.39 (s, 3H), 2.55 (dt, J=12.7,8.9Hz, 1H), 2.48-2.37 (m, 1H), 2.32 (dd, J=13.0,3.4Hz, 1H), 2.26-2.15 (m, 1H), 2.11-2.06 (m, 1H), 2.06 (s, 3H), 1.96-1.87 (m, 1H), 1.85 (dd, J=14.7,4.2Hz, 1H), 1.72-1.59 (m, 4H), 1.52 (dd, J=14.6,12.3Hz, 1H), 1.45-1.34 (m, 5H), 1.30 (dd, J=12.3, 7.0Hz, 1H), 0.98 (s, 3H), 0.94 (d, J=6.6Hz, 3H)；13C NMR (125MHz, CDCl3) δ 196.2,170.9, 170.0,124.0,108.8,80.3,75.8,74.2,68.2,59.1,56.9,56.0,52.1,49.7,45.0,43.2, 41.3,40.7,40.2,38.8,33.1,26.6,26.4,20.9,18.9,13.3,11.5.
The synthetic route of compound L is as follows：
(10) at 0 DEG C, compound L (0.88g, 1.85mmol) is dissolved in analysis pure tetrahydrofuran (32.0mL) and water In (8.0mL), it is slowly added to sodium borohydride (0.21g, 5.54mmol), stirring to complete reaction about 1 hour, then uses saturation Reaction is quenched in ammonium chloride solution, and with ethyl acetate dilution, extraction, organic phase uses saturated ammonium chloride solution, saturated salt solution successively Solution washs, and is dried with anhydrous sodium sulfate solid, filtering, then is under reduced pressure spin-dried for organic solvent, obtains containing compound M's 4th crude product.
(11) at -78 DEG C, the 4th crude product is dissolved in anhydrous tetrahydro furan (30mL), under continuous agitation The tetrahydrofuran solution (a concentration of 1.0mol/L, 1.94mmol) of bis- (trimethylsilyl) potassamides of 1.94mL is added, instead After answering 6 minutes, carbon disulfide (0.42mL, 6.98mmol) is added, it is small to continue stirring 1 for iodomethane (0.43mL, 6.98mmol) When, reaction then is quenched with saturated ammonium chloride solution, after ethyl acetate dilution, extraction, organic phase uses saturated ammonium chloride successively Solution, saturated common salt aqueous solution washing, is dried with anhydrous sodium sulfate solid, filtering, then is under reduced pressure spin-dried for organic solvent, is obtained To the 5th crude product containing compound N.
(12) at room temperature, the 5th crude product is dissolved in dry toluene, after being vented 15 minutes with argon gas ball, is sequentially added Azodiisobutyronitrile (68.0mg, 0.41mmol) and tri-n-butyl tin hydrogen (4.85mL, 18.5mmol), are then heated to 80 DEG C, stirring about 1 hour, is then cooled to room temperature to the reaction was complete, after reaction solution is spin-dried for concentration, gained liquid layer of silica gel Analysis isolates and purifies, and obtains compound O, about 140mg, yield 51%.
Wherein, the detection data of compound O is as follows：(c 1.10, MeOH)；1H NMR (500MHz, CDCl3) δ 5.67 (d, J=6.5Hz, 1H), 5.36 (d, J=5.1Hz, 1H), 4.42 (dd, J=7.5,5.1Hz, 1H), 4.11 (s, 1H), 4.04 (dd, J=10.9,4.0Hz, 1H), 3.89 (dd, J=10.9,7.0Hz, 1H), 3.43 (s, 3H), 3.38 (s, 3H), 2.68 (dd, J=17.0,4.7Hz, 1H), 2.43-2.32 (m, 1H), 2.32-2.23 (m, 1H), 2.18-2.10 (m, 1H), 2.06 (s, 3H), 2.04-1.93 (m, 3H), 1.89-1.80 (m, 2H), 1.70 (dd, J=17.4,5.5Hz, 1H), 1.67-1.60 (m, 2H), 1.56-1.49 (m, 1H), 1.44-1.24 (m, 7H), 0.93 (s, 3H), 0.92 (d, J=5.6Hz, 3H)；13C NMR (125MHz, CDCl3) δ 171.2,144.1,117.6,108.9,74.8,74.5,73.3,69.0,59.8, 56.9,56.0,52.2,48.8,48.1,44.9,43.2,40.6,40.2,39.1,38.8,34.1,27.6,26.7,21.1, 19.0,13.4,11.4.The synthetic route of compound O is as follows：
(13) at 0 DEG C, compound O (250.0mg, 0.54mmol) is dissolved in anhydrous methylene chloride (10mL), successively 2,4,6- trimethylpyridines (360 μ L, 2.70mmol), thionyl chloride (120 μ L, 1.62mmol) and pyrrole are added into reaction system Pyridine (220 μ L, 2.70mmol), and stirring about half an hour, is quenched instead to the reaction was complete with saturated sodium bicarbonate solution at 0 DEG C Ying Hou, with ether dilution, extraction, organic phase uses hydrochloric acid, the saturated common salt water washing of 1mol/L successively, dry with anhydrous sodium sulfate It is dry, filtering.After organic solvent is spin-dried under reduced pressure, the 6th crude product containing compound P is obtained.
(14) at room temperature, the 6th crude product is dissolved in anhydrous ethylamine (5mL), be carefully added into lithium metal (75.6mg, 10.8mmol), solution turned blue after ten minutes is stirred, continues to be stirred at room temperature 45 minutes, is then cooled to -78 DEG C, is added successively Enter isoprene (1mL) and reaction is quenched in saturated ammonium chloride solution (3mL), is subsequently added into ether dilution, extraction reaction, organic phase Saturated ammonium chloride solution, the washing of saturated common salt aqueous solution is used to be dried with anhydrous sodium sulfate solid, filtering successively.Under reduced pressure will Organic solvent is spin-dried for, and gained liquid silica gel column chromatography separating purification obtains compound Q, about 99mg, yield 51%.
The detection data of compound Q is as follows：(c 1.00, MeOH)；1H NMR (500MHz, MeOD-d4)δ 5.50 (t, J=7.5Hz, 1H), 5.12-5.06 (m, 1H), 3.74-3.66 (m, 1H), 3.62 (dd, J=10.7,3.4Hz, 1H), 3.57 (dd, J=10.7,3.2Hz, 1H), 3.49 (dd, J=10.7,6.9Hz, 1H), 3.26 (dd, J=10.6, 7.1Hz, 1H), 2.82-2.73 (m, 1H), 2.73-2.64 (m, 1H), 2.49 (ddd, J=13.3,11.4,6.0Hz, 1H), 2.42-2.36 (m, 1H), 2.36-2.28 (m, 2H), 2.26-2.17 (m, 1H), 2.06-1.98 (m, 1H), 1.97-1.85 (m, 2H), 1.72-1.64 (m, 2H), 1.60-1.48 (m, 4H), 1.41-1.30 (m, 4H), 1.04 (d, J=6.6Hz, 3H), 0.67 (s, 3H)；13C NMR (125MHz, MeOD-d4) δ 147.3,140.4,122.8,117.6,66.4,64.5,63.8,55.2, 52.7,51.2,43.8,43.4,39.5,39.4,39.2,35.8,35.7,31.7,28.4,26.8,23.0,16.1,11.3.Change The synthetic route for closing object Q is as follows：
(15) at room temperature, compound Q (70.0mg, 194 μm of ol) is dissolved in dichloromethane (20mL), carbonic acid is added Then the buffer solution (pH=8.6,20mL) of hydrogen sodium and potassium carbonate sequentially adds tetrabutylammonium chloride (215.0mg, 776 μ Mol), 2,2,6,6- tetramethyl piperidine oxides (15.1mg, 97 μm of ol) and N- chlorosuccinimides (103.0mg, 776 μ Mol), with thin-layered chromatography detect react, the reaction was complete about 1 hour, then with ethyl acetate dilution, extraction, organic phase again according to Secondary saturated sodium thiosulfate, saturated common salt water washing, are dried with anhydrous sodium sulfate.After organic phase is concentrated under reduced pressure, residue is used Silica gel post separation obtains compound R, 48mg, yield 70%.
The analysis data of compound R:(c 0.40, CHCl3)；1H NMR (500MHz, CDCl3)δ9.77 (d, J=2.1Hz, 1H), 9.61 (d, J=3.1Hz, 1H), 5.58 (t, J=7.3Hz, 1H), 5.31-5.17 (m, 1H), 3.86 (t, J=10.7Hz, 1H), 3.49 (ddd, J=11.0,4.1,2.2Hz, 1H), 2.90-2.80 (m, 1H), 2.58 (ddd, J= 13.4,11.4,6.1Hz, 1H), 2.50 (d, J=12.7Hz, 1H), 2.46-2.26 (m, 5H), 2.03-1.92 (m, 3H), 1.87-1.78 (m, 1H), 1.74-1.55 (m, 4H), 1.50-1.38 (m, 3H), 1.16 (d, J=6.9Hz, 3H), 0.68 (s, 3H)；13C NMR (125MHz, CDCl3) δ 204.8,203.2,145.9,142.6,119.0,114.5,64.3,55.0,51.2, 51.2,50.1,49.7,44.7,43.9,39.0,36.2,35.3,31.4,28.4,26.4,23.5,13.6,12.7.Compound R Synthetic route it is as follows：
(16) compound R (40.0mg, 0.11mmol) is dissolved in anhydrous methylene chloride (5mL), then at -78 DEG C Under, sequentially add 2,6- lutidines (80.0 μ L, 0.66mmol) and triethyl group silicon substrate triflate (80.0 μ L, 0.33mmol), after stirring 0.5 hour, saturated sodium bicarbonate solution is added, reaction is quenched, reacted with ethyl acetate dilution, extraction Liquid, organic phase are dried through saturated common salt water washing, then with anhydrous sodium sulfate, filtering, after organic phase is concentrated under reduced pressure, residue silica gel Column chromatographic isolation and purification obtains compound S, 45.0mg, yield 86%.
The detection data of compound S is as follows：(c 0.31, CHCl3)；1H NMR (500MHz, CDCl3)δ 9.75 (s, 1H), 9.59 (s, 1H), 5.54 (t, J=7.3Hz, 1H), 5.23 (s, 1H), 3.80 (t, J=11.3Hz, 1H), 3.48 (d, J=11.1Hz, 1H), 2.89-2.76 (m, 1H), 2.61 (td, J=12.4,6.1Hz, 1H), 2.49 (d, J= 12.6Hz, 1H), 2.42-2.16 (m, 5H), 2.00-1.82 (m, 4H), 1.72-1.53 (m, 4H), 1.48-1.36 (m, 3H), 1.14 (d, J=6.8Hz, 3H), 0.94 (t, J=7.9Hz, 9H), 0.66 (s, 3H), 0.58 (q, J=8.0Hz, 6H)；13C NMR (125MHz, CDCl3) δ 204.8,203.2,145.8,142.5,119.4,114.5,64.5,55.0,51.2,51.2,50.3, 49.8,44.7,44.4,39.1,36.9,35.9,31.5,28.4,26.4,23.5,13.6,12.7,6.9,4.7.Compound S's Synthetic route is as follows：
(17) at room temperature, compound S (40.0mg, 95.6 μm of ol) is dissolved in anhydrous tertiary butanol (5mL), is removed with argon gas Then the tetrahydrofuran solution (a concentration of 1.8mol/L, 0.288mmol) of the potassium tert-butoxide of 160.0 μ L is added in oxygen about 10 minutes, Then it changes oxygen to blow about 10 minutes, then reaction is quenched with saturated ammonium chloride solution, reaction solution, organic phase is extracted with ethyl acetate It is dried, is filtered with anhydrous sodium sulfate after saturated common salt water washing, after organic phase is concentrated under reduced pressure, the separation of residue silica gel column chromatography Purifying obtains compound T, 24mg, yield 56%.
The detection data of compound T is as follows：(c 0.60, CHCl3)；1H NMR (500MHz, CDCl3)δ 5.62 (s, 1H), 5.60 (t, J=7.4Hz, 1H), 3.47 (t, J=11.0Hz, 1H), 2.83 (dd, J=12.3,5.6Hz, 2H), 2.79-2.70 (m, 2H), 2.62-2.48 (m, 3H), 2.29-2.21 (m, 2H), 2.21-2.11 (m, 2H), 2.18 (s, 3H), 1.91-1.76 (m, 2H), 1.77-1.61 (m, 5H), 0.99 (t, J=7.9Hz, 9H), 0.66 (s, 3H), 0.63 (q, J= 8.0Hz, 6H)；13C NMR (125MHz, CDCl3) δ 208.7,205.1,155.8,145.4,125.6,122.8,65.0,63.5, 55.8,53.8,49.0,46.6,42.0,38.1,36.8,31.5,27.6,27.6,23.2,22.5,13.8,6.9,4.7.Chemical combination The synthetic route of object T is as follows：
(18) compound U (108.0mg, 0.23mmol) is dissolved in anhydrous tetrahydro furan (50mL), at -78 DEG C, is added Enter the hexane solution (concentration 1.6mol/L, 0.18mmol) of the n-BuLi of 112.5 μ L, and half an hour reacted at -78 DEG C, Then anhydrous tetrahydro furan (3mL) solution the reaction was continued 10min of compound T (20.0mg, 45.2 μm of ol) is added dropwise, then Reaction is quenched with methanol (0.1mL, 2.47mmol), then is warming up to room temperature, the tetrabutyl fluorination of 0.54mL is added to reaction system The reaction was continued for ammonium (1.0mol/L, 0.54mmol), and the reaction was complete after 1 hour for reaction, is then quenched instead with saturated ammonium chloride solution It answers, reaction solution is extracted with ethyl acetate, organic phase uses saturated ammonium chloride solution, saturated common salt aqueous solution to wash successively, and use is anhydrous Solid sodium sulfate is dried, filtering.Organic solvent is spin-dried under reduced pressure, gained liquid silica gel column chromatography obtains sterides compound Object cyclocitrinol, 15.0mg, yield 84%.
The detection data of steroidal compounds cyclocitrinol is as follows：(c 0.45, MeOH)；1H NMR (500MHz, DMSO-d6) δ 5.64 (dd, J=15.6,1.3Hz, 1H), 5.54 (dd, J=8.1,6.4Hz, 1H), 5.50 (dd, J =15.6,5.4Hz, 1H), 5.38 (s, 1H), 4.60 (d, J=4.4Hz, 1H), 4.55 (d, J=4.6Hz, 1H), 4.21 (s, 1H), 4.14-4.05 (m, 1H), 3.17-3.05 (m, 1H), 2.79 (dd, J=12.0,5.4Hz, 1H), 2.68-2.66 (m, 1H), 2.62 (brd, J=12.7Hz, 1H), 2.47 (brs, 2H), 2.38-2.28 (ddd, J=13.2,11.1,6.2,1H), 2.16-2.02 (m, 3H), 1.83-1.71 (m, 1H), 1.71-1.33 (m, 8H), 1.20 (s, 3H), 1.09 (d, J=6.4Hz, 3H), 0.71 (s, 3H)；13C NMR (500MHz, DMSO-d6) δ 204.1,157.1,145.7,136.0,130.7,124.5, 121.9,73.3,66.2,63.1,60.0,55.2,53.2,48.1,45.9,41.3,38.8,35.9,28.9,27.5,27.1, 24.0,22.3,22.1,14.3.The synthetic route of steroidal compounds cyclocitrinol is as follows：
Embodiment 2
The step of preparation method of the steroidal compounds of the present embodiment, is as follows：
(1) at -78 DEG C, compound A (20.0g, 78.6mmol) is dissolved in anhydrous ether (300mL), is changed Close the diethyl ether solution of object A；At -78 DEG C, under continuous agitation, diisopropyl is added in the diethyl ether solution of compound A It in lithium amide (98.25mL, 2.0mol/L), and is stirred to react at such a temperature 4 hours, trim,ethylchlorosilane is then added (13.63mL, 157.2mmol) continues to be stirred to react at such a temperature, and chromatographic sheet detection is used in combination until the reaction is complete, and about 2 Hour, reaction is quenched with saturated ammonium chloride solution, with ether dilution, extraction reaction solution, after water phase is extracted 2 times with ether, merges Organic phase, and organic phase is used into saturated ammonium chloride and saturated common salt water washing successively, then with anhydrous sodium sulfate dry filter, subtract Pressure is spin-dried for organic solvent, and with short column of silica gel, (eluent is that volume ratio is 1 to obtained liquid:10:0.01 ethyl acetate, just The mixture of hexane and triethylamine) quickly elution, obtain the first crude product containing compound B (silyl enol ether), about 25.8g.
(2) the first crude product of above-mentioned gained is dissolved in analytically pure n,N-Dimethylformamide (100mL), in room temperature Under, 2- iodosobenzoic acids (54.99g, 196.5mmol) are added, continue to be stirred to react, are used in combination chromatographic sheet detection until the One crude product disappear, about 1 hour, then with ether dilution, extraction reaction solution, organic phase with saturated common salt water washing for several times, then It filters, is under reduced pressure spin-dried for organic solvent, gained liquid silica gel column layer after organic phase is dried with anhydrous sodium sulfate solid Analysis separation, obtains compound C, about 12.0g, yield 61%.The detection data of the compound C of the present embodiment and 1 phase of embodiment Together, details are not described herein.The synthetic route of compound C is as follows：
(3) iodine (20.1g, 79.3mmol) is dissolved in pyridine (31.93mL, 396.5mmol), the pyridine for obtaining iodine is molten Liquid；Compound C (20.0g, 79.3mmol) is dissolved in anhydrous methylene chloride (300mL), azido three is added under the conditions of 0 DEG C Methyl-monosilane (10.43mL, 79.3mmol), and stir 1 hour at such a temperature, the pyridine of iodine is then slowly added dropwise at 0 DEG C Solution, reaction clear-cutting forestland are stirred overnight (about 12 hours) to the reaction was complete, reaction system are then down to 0 DEG C again to room temperature, Saturated sodium thiosulfate is added, reaction is quenched, with ether dilution, extraction reaction system, organic phase uses saturated ammonium chloride, satisfies successively And brine It, anhydrous sodium sulfate solid dry filter, then be under reduced pressure spin-dried for organic solvent, gained liquid silicagel column Chromatography, obtains compound D, about 12.9g, yield 43%.The detection data of the compound D of the present embodiment is same as Example 1, This is repeated no more.The synthetic route of compound D is as follows：
(4) at room temperature, alkenyl iodine D (8.40g, 22.2mmol) is dissolved in analytically pure N-methyl pyrrolidones (50mL) In, then sequentially added in the environment of nitrogen protection CuTC (174.766g, 33.3mmol), lithium acetate (2.93g, 44.4mmol), tetra-triphenylphosphine palladium (256mg, 0.22mmol), compound E (11.1g, 22.2mmol), and be stirred at room temperature Reaction 10 hours, obtained reaction solution dilutes with ether, extraction, and organic phase uses saturated common salt water washing 3 times, with anhydrous sulphur successively Sour sodium solid drying, is then filtered, then be under reduced pressure spin-dried for organic solvent, gained liquid is detached with silica gel column chromatography, is obtained Compound F, about 8.11g, yield 79%.The detection data of the compound F of the present embodiment is same as Example 1, no longer superfluous herein It states.The synthetic route of compound F is as follows：
(5) at room temperature, compound F (8.53g, 18.3mmol) is dissolved in the pure methanol (200mL) of analysis, adds six Be hydrated Nickel Chloride (15.0g, 54.9mmol), be then cooled to -78 DEG C, be carefully added into sodium borohydride (3.48g, 91.5mmol), and at -78 DEG C it is stirred to react until reaction system is slowly increased to room temperature, about 3 hours.Then ethyl acetate is used (500mL) diluting reaction system adds diatomite (30g), is filtered after stirring half an hour, mother liquid obtained successively with saturation chlorination Organic solvent after filtering, is spin-dried for, obtains by ammonium salt solution, the washing of saturated common salt aqueous solution, anhydrous sodium sulfate drying under reduced pressure Liquid silica gel column chromatography obtains compound G, about 4.00g, yield 47%.The detection data and reality of the compound G of the present embodiment Apply that example 1 is identical, and details are not described herein.The synthetic route of compound G is as follows：
(6) at -78 DEG C, compound H (6.33g, 19.8mmol) is dissolved in anhydrous ether (50mL), obtains compound Then the diethyl ether solution of H adds the pentane solution (molar concentration 1.3mol/L) of the tert-butyl lithium of 22.85mL (29.7mmol) Enter into the diethyl ether solution of compound H, and be stirred to react at -78 DEG C 45 minutes, be subsequently added into compound G (2.3g, Anhydrous ether (20mL) solution 4.95mmol), continues to be stirred to react about 2 hours, then reaction is quenched with saturated ammonium chloride solution, With ether dilution, extraction reaction solution, organic phase merges, and uses saturated ammonium chloride and saturated common salt water washing organic phase successively, then will Organic solvent, is spin-dried for by organic phase anhydrous sodium sulfate dry filter under reduced pressure, and obtained liquid silica gel column chromatography obtains Compound I, about 2.55g, yield 73%.The detection data of the compound I of the present embodiment is same as Example 1, no longer superfluous herein It states.The synthetic route of compound I is as follows：
(7) compound I (1.93g, 2.73mmol) is dissolved in analysis pure tetrahydrofuran (60mL), in the condition of room temperature Under, the tetrahydrofuran solution (molar concentration 1.0mol/L) of the tetrabutyl ammonium fluoride (8.19mmol) of 8.19mL is added, continues to stir 2 hours are mixed to the reaction was complete, reaction system is then cooled to 0 DEG C, sequentially adds water (20mL), sodium acetate (2.73mmol), sodium bicarbonate (2.73mmol) and N- bromo-succinimides (4.095mmol), and reacted to anti-at 0 DEG C Should be complete, about 45 minutes, then reaction is quenched with saturated sodium thiosulfate solution, with ethyl acetate dilution, extraction, organic phase is successively With saturated ammonium chloride solution, the washing of saturated common salt aqueous solution is dried, filtering with anhydrous sodium sulfate solid.It under reduced pressure will be organic Solvent is spin-dried for, and obtains the second crude product containing compound J.
(8) at room temperature, the second crude product is dissolved in anhydrous methylene chloride (50mL), sequentially adds 4- dimethylamino pyrroles Pyridine (0.32g, 2.73mmol), 2,2,6,6- tetramethyl piperidines (1.84mL, 10.9mmol), acetic anhydride (0.92mL, 8.19mmol), reaction is to the reaction was complete, about 1 hour, and after reaction system short column of silica gel fast filtering, filtrate is revolved under reduced pressure Dry concentration, obtains the third crude product containing compound K.
(9) third crude product is dissolved in after anhydrous methylene chloride (750mL) and is transferred to 1L tube sealing bottles, be added 2,2,6,6- tetra- Methyl piperidine (0.69mL, 4.01mmol).Be heated to 145 DEG C reaction 12 hours after, be cooled to room temperature, under reduced pressure will be organic molten Agent is spin-dried for, and gained liquid silica gel column chromatography obtains compound L, about 0.82g, yield 63%.The compound L of the present embodiment Detection data it is same as Example 1, details are not described herein.The synthetic route of compound L is as follows：
(10) at 0 DEG C, compound L (0.88g, 1.85mmol) is dissolved in analysis pure tetrahydrofuran (32.0mL) and water In (8.0mL), it is slowly added to sodium borohydride (1.85mmol), stirring about 2 hours, then uses saturated ammonium chloride to complete reaction Reaction is quenched in solution, and after ethyl acetate dilution, extraction, organic phase uses saturated ammonium chloride solution, saturated common salt aqueous solution successively Washing is dried with anhydrous sodium sulfate solid, filtering, then is under reduced pressure spin-dried for organic solvent, obtains the 4th containing compound M Crude product.
(11) at -78 DEG C, the 4th crude product is dissolved in anhydrous tetrahydro furan (30mL), under continuous agitation The tetrahydrofuran solution (a concentration of 1.0mol/L, 1.85mmol) of bis- (trimethylsilyl) potassamides of 1.85mL is added, instead Carbon disulfide (0.23mL, 3.70mmol) and iodomethane (0.24mL, 3.70mmol) should be added, continue stirring 1.5 after ten minutes Hour, reaction then is quenched with saturated ammonium chloride solution, after ethyl acetate dilution, extraction, organic phase is successively with saturation chlorination Ammonium salt solution, saturated common salt aqueous solution washing, is dried with anhydrous sodium sulfate solid, filtering, then is under reduced pressure spin-dried for organic solvent, Obtain the 5th crude product containing compound N.
(12) at room temperature, the 5th crude product is dissolved in dry toluene, after being vented 15 minutes with argon gas ball, is sequentially added Azodiisobutyronitrile (31.0mg, 0.185mmol) and tri-n-butyl tin hydrogen (1.94mL, 7.4mmol), are then heated to 100 DEG C, stirring about 1.5 hours, is then cooled to room temperature to the reaction was complete, after reaction solution is spin-dried for concentration, gained liquid silica gel Chromatography purifies, and obtains compound O, about 118mg, yield 43%.The detection data and embodiment of the compound O of the present embodiment 1 is identical, and details are not described herein.The synthetic route of compound O is as follows：
(13) at 0 DEG C, compound O (250.0mg, 0.54mmol) is dissolved in anhydrous methylene chloride (10mL), successively 2,4,6- trimethylpyridines (576 μ L, 4.32mmol), thionyl chloride (180 μ L, 1.08mmol) and pyrrole are added into reaction system Pyridine (176 μ L, 2.16mmol), and stirring about 12 minutes, is quenched instead to the reaction was complete with saturated sodium bicarbonate solution at 0 DEG C Ying Hou, with ether dilution, extraction, organic phase uses hydrochloric acid, the saturated common salt water washing of 1mol/L successively, dry with anhydrous sodium sulfate It is dry, filtering.After organic solvent is spin-dried under reduced pressure, the 6th crude product containing compound P is obtained.
(14) at room temperature, the 6th crude product is dissolved in anhydrous ethylamine (5mL), be carefully added into lithium metal (38.0mg, 5.40mmol), solution turned blue after ten minutes is stirred, continues to be stirred at room temperature 1 hour, is then cooled to -78 DEG C, sequentially adds Reaction is quenched in isoprene (1mL) and saturated ammonium chloride solution (3mL), be subsequently added into ether dilution, extraction reaction, organic phase according to It is secondary that saturated ammonium chloride solution, the washing of saturated common salt aqueous solution is used to be dried with anhydrous sodium sulfate solid, filtering.To have under reduced pressure Solvent is spin-dried for, and gained liquid silica gel column chromatography separating purification obtains compound Q, about 79mg, yield 41%.The present embodiment Compound Q detection data it is same as Example 1, details are not described herein.The synthetic route of compound Q is as follows：
(15) at room temperature, compound Q (70.0mg, 194 μm of ol) is dissolved in dichloromethane (20mL), carbonic acid is added The buffer solution (pH=8.6,20mL) of hydrogen sodium and potassium carbonate, then sequentially adds tetrabutyl chlorination under continuous agitation Ammonium (107.5mg, 388 μm of ol), 2,2,6,6- tetramethyl piperidine oxides (6.0mg, 38.8 μm of ol) and N- chloros succinyl are sub- Amine (56.5mg, 388 μm of ol) is detected with thin-layered chromatography and is reacted, and the reaction was complete about 2 hours, then with ethyl acetate dilution, extraction It takes, then uses saturated sodium thiosulfate, saturated common salt water washing successively, dried with anhydrous sodium sulfate.It is residual after organic phase is concentrated under reduced pressure Object silica gel post separation is stayed, compound R, 41mg, yield 60% are obtained.The detection data of the compound R of the present embodiment and implementation Example 1 is identical, and details are not described herein.The synthetic route of compound R is as follows：
(16) compound R (40.0mg, 0.11mmol) is dissolved in anhydrous methylene chloride (5mL), then at -78 DEG C Under, sequentially add 2,6- lutidines (67.0 μ L, 0.55mmol) and triethyl group silicon substrate triflate (107.0 μ L, 0.44mmol), after stirring 1 hour, saturated sodium bicarbonate solution is added, reaction is quenched, with ethyl acetate dilution, extract reaction solution, Organic phase is dried through saturated common salt water washing, then with anhydrous sodium sulfate, filtering, after organic phase is concentrated under reduced pressure, residue silicagel column Chromatography purifies, and obtains compound S, 45.5mg, yield 87%.The detection data of the compound S of the present embodiment and embodiment 1 Identical, details are not described herein.The synthetic route of compound S is as follows：
(17) at room temperature, compound S (40.0mg, 95.6 μm of ol) is dissolved in anhydrous tertiary butanol (5mL), is removed with argon gas Then oxygen about 10 minutes is added the tetrahydrofuran solution (a concentration of 1.8mol/L, 191 μm of ol) of the potassium tert-butoxide of 106.1 μ L, connects It and changes oxygen air blowing about 6 minutes, then reaction is quenched with saturated ammonium chloride solution, reaction solution, organic phase warp is extracted with ethyl acetate It is dried, is filtered with anhydrous sodium sulfate after saturated common salt water washing, after organic phase is concentrated under reduced pressure, the separation of residue silica gel column chromatography is pure Change, obtains compound T, 17.6mg, yield 41%.The detection data of the compound T of the present embodiment is same as Example 1, herein It repeats no more.The synthetic route of compound T is as follows：
(18) compound U (85.0mg, 180.8 μm of ol) is dissolved in anhydrous tetrahydro furan (50mL), at -78 DEG C, is added Enter the hexane solution (concentration 1.6mol/L, 135.6 μm of ol) of 84.75 μ L n-BuLis, and 45min is reacted at -78 DEG C, so After anhydrous tetrahydro furan (3mL) solution the reaction was continued 6min of compound T (20.0mg, 45.2 μm of ol) is added dropwise, then use Reaction is quenched in methanol (18.2 μ L, 452 μm of ol), then is warming up to room temperature, and the tetrabutyl ammonium fluoride of 678 μ L is added to reaction system (1.0mol/L, 678.0 μm of ol) the reaction was continued, and the reaction was complete after 1.5 hours for reaction, is then quenched instead with saturated ammonium chloride solution It answers, reaction solution is extracted with ethyl acetate, organic phase uses saturated ammonium chloride solution, saturated common salt aqueous solution to wash successively, and use is anhydrous Solid sodium sulfate is dried, filtering.Organic solvent is spin-dried under reduced pressure, gained liquid silica gel column chromatography obtains sterides compound Object cyclocitrinol, 13.0mg, yield 73%.The detection data of the steroidal compounds cyclocitrinol of the present embodiment with Embodiment 1 is identical, and details are not described herein.The synthetic route of steroidal compounds cyclocitrinol is as follows：
Embodiment 3
The step of preparation method of the steroidal compounds of the present embodiment, is as follows：
(1) at -78 DEG C, compound A (20.0g, 78.6mmol) is dissolved in anhydrous tetrahydro furan (300mL), is obtained To the tetrahydrofuran solution of compound A；At -78 DEG C, lithium diisopropylamine is added in the tetrahydrofuran solution of compound A In (39.3mL, 2.0mol/L), and be stirred to react 3 hours at such a temperature, be then added trim,ethylchlorosilane (6.815mL, 78.6mmol), continue to be stirred to react at such a temperature, chromatographic sheet detection is used in combination until the reaction is complete, about 4 hours, with full Reaction is quenched with ammonium chloride solution, with ether dilution, extraction reaction solution, organic phase uses saturated ammonium chloride and saturated salt solution successively Washing, then with anhydrous sodium sulfate dry filter, organic solvent is spin-dried under decompression, with short column of silica gel, (eluent is obtained liquid Volume ratio is 1:10:0.01 ethyl acetate, the mixture of n-hexane and triethylamine) quickly elution, it obtains containing compound B First crude product of (silyl enol ether), about 25.4g.
(2) the first crude product of above-mentioned gained is dissolved in analytically pure n,N-Dimethylformamide (100mL), in room temperature Under, 2- iodosobenzoic acids (22g, 78.6mmol) are added, continue to be stirred to react, chromatographic sheet detection is used in combination until raw material disappears It loses, about 5 hours, is then diluted with ether, extraction reaction solution, organic phase for several times, then by organic phase is used with saturated common salt water washing It filters, is under reduced pressure spin-dried for organic solvent, gained liquid is detached with silica gel column chromatography, is obtained after the drying of anhydrous sodium sulfate solid Compound C, about 10.5g, yield 53%.Wherein, the detection data of compound C is same as Example 1, and details are not described herein. The synthetic route of compound C is as follows：
(3) iodine (100.6g, 396.5mmol) is dissolved in pyridine (63.8mL, 793mmol), the pyridine for obtaining iodine is molten Liquid；Compound C (20.0g, 79.3mmol) is dissolved in anhydrous chloroform (300mL), azido trimethyl is added under the conditions of 0 DEG C Silane (52.1mL, 396.5mmol), and stir 5 hours at such a temperature, the pyridine solution of iodine is then slowly added dropwise at 0 DEG C, Clear-cutting forestland is reacted to room temperature, is stirred overnight (about 14 hours) to the reaction was complete, reaction system is then down to 0 DEG C again, be added Reaction is quenched in saturated sodium thiosulfate, and with ether dilution, extraction reaction system, organic phase uses saturated ammonium chloride, saturation food successively Salt water washing, anhydrous sodium sulfate solid dry filter, then be under reduced pressure spin-dried for organic solvent, gained liquid silica gel column layer Analysis, obtains compound D, about 19.1g, yield 67%.The detection data of compound D is same as Example 1, and details are not described herein. The synthetic route of compound D is as follows：
(4) at room temperature, compound D (8.40g, 22.2mmol) is dissolved in analytically pure N-methyl pyrrolidones (50mL) In, then sequentially added in the environment of nitrogen protection CuTC (4.23g, 22.2mmol), lithium acetate (5.86g, 88.8mmol), Tetra-triphenylphosphine palladium (1.30g, 1.11mmol), compound E (33.4g, 44.4mmol), and reaction 9 hours is stirred at room temperature, Obtained reaction solution is diluted with ether, is extracted, and organic phase uses saturated common salt water washing 3 times, is dry with anhydrous sodium sulfate solid successively It is dry, it then filters, then be under reduced pressure spin-dried for organic solvent, gained liquid is detached with silica gel column chromatography, obtains compound F, about 8.73g, yield 85%.The detection data of the compound F of the present embodiment is same as Example 1, and details are not described herein.Compound F Synthetic route it is as follows：
(5) at room temperature, compound F (8.53g, 18.3mmol) is dissolved in the pure methanol (200mL) of analysis and water (20mL) Mixed solution in, add six hydration Nickel Chlorides (40.0g, 146.4mmol), be then cooled to -78 DEG C, be carefully added into boron Sodium hydride (10.4g, 274.5mmol), and be stirred to react at -78 DEG C until reaction system is slowly increased to room temperature, about 1.5 is small When.Then ethyl acetate (500mL) diluting reaction system is used, diatomite (50g) is added, is filtered after stirring half an hour, gained Mother liquor is washed with saturated ammonium chloride solution, saturated common salt aqueous solution successively, anhydrous sodium sulfate drying, after filtering, under reduced pressure will Organic solvent is spin-dried for, and obtained liquid silica gel column chromatography obtains compound G, about 5.44g, yield 64%.The change of the present embodiment The detection data for closing object G is same as Example 1, and details are not described herein.The synthetic route of compound G is as follows：
(6) at -78 DEG C, compound H (4.75g, 14.85mmol) is dissolved in anhydrous ether (50mL), obtains chemical combination Then the diethyl ether solution of compound H is added to positive the penta of the tert-butyl lithium (22.23mmol) of 17.1mL by the diethyl ether solution of object H In alkane solution (molar concentration 1.3mol/L), and be stirred to react at -78 DEG C 1 hour, be subsequently added into compound G (2.3g, Anhydrous ether (20mL) solution 4.95mmol), continues to be stirred to react about 1 hour, then reaction is quenched with saturated ammonium chloride solution, With ether dilution, extraction reaction solution, organic phase uses saturated ammonium chloride and saturated common salt water washing organic phase successively, then by organic phase With anhydrous sodium sulfate dry filter, organic solvent is spin-dried under reduced pressure, obtained liquid silica gel column chromatography obtains compound I, about 2.76g, yield 79%.The detection data of the compound I of the present embodiment is same as Example 1, and details are not described herein.Chemical combination The synthetic route of object I is as follows：
(7) mixing that compound I (1.93g, 2.73mmol) is dissolved in analysis pure tetrahydrofuran (60mL) and water (6mL) is molten In liquid, then under conditions of room temperature, the tetrahydrofuran solution that the tetrabutyl ammonium fluoride (10.92mmol) of 10.92mL is added (rubs You are concentration 1.0mol/L), continue stirring 1 hour to the reaction was complete, reaction system is then cooled to 0 DEG C, sequentially adds water (20mL), sodium acetate (8.19mmol), sodium bicarbonate (8.19mmol) and N- bromo-succinimides (5.46mmol), and 0 Reaction is to the reaction was complete at DEG C, about 1 hour, then reaction is quenched with saturated sodium thiosulfate solution, with ethyl acetate dilution, extraction It takes, organic phase uses saturated ammonium chloride solution, the washing of saturated common salt aqueous solution to be dried with anhydrous sodium sulfate solid, filtering successively. Organic solvent is spin-dried under decompression, obtains the second crude product containing compound J.
(8) at room temperature, the second crude product is dissolved in anhydrous acetonitrile (50mL), sequentially adds 4-dimethylaminopyridine (0.16g, 1.36mmol), 2,2,6,6- tetramethyl piperidines (1.84mL, 10.9mmol), acetic anhydride (1.23mL, 10.92mmol), reaction is to the reaction was complete, about 1 hour, and after reaction system short column of silica gel fast filtering, filtrate is revolved under reduced pressure Dry concentration, obtains the third crude product containing compound K.
(9) third crude product is dissolved in after dry toluene (750mL) and is transferred to 1L tube sealing bottles, 2,2,6,6- tetramethyls are added Piperidines (1.84mL, 10.92mmol).Be heated to 160 DEG C reaction 10 hours after, be cooled to room temperature, under reduced pressure by organic solvent It is spin-dried for, gained liquid silica gel column chromatography obtains compound L, about 0.79g, yield 61%.The compound L of the present embodiment Detection data is same as Example 1, and details are not described herein.The synthetic route of compound L is as follows：
(10) at 0 DEG C, compound L (0.88g, 1.85mmol) is dissolved in analysis pure tetrahydrofuran (32.0mL) and water In (16.0mL), it is slowly added to sodium borohydride (3.7mmol), stirring about 2 hours, then uses saturated ammonium chloride to complete reaction Reaction is quenched in solution, and after ethyl acetate dilution, extraction, organic phase uses saturated ammonium chloride solution, saturated common salt aqueous solution successively Washing is dried with anhydrous sodium sulfate solid, filtering, then is under reduced pressure spin-dried for organic solvent, obtains the 4th containing compound M Crude product.
(11) at -78 DEG C, the 4th crude product is dissolved in anhydrous ether (30mL), is added under continuous agitation The tetrahydrofuran solution (a concentration of 1.0mol/L, 2.775mmol) of bis- (trimethylsilyl) potassamides of 2.775mL, reaction 1 After hour, carbon disulfide (0.89mL, 14.8mmol) and iodomethane (0.90mL, 14.8mmol) is added, continues stirring 2 hours, Then reaction is quenched with saturated ammonium chloride solution, after ethyl acetate dilution, extraction, organic phase uses saturated ammonium chloride molten successively Liquid, saturated common salt aqueous solution washing, is dried with anhydrous sodium sulfate solid, filtering, then is under reduced pressure spin-dried for organic solvent, is obtained The 5th crude product containing compound N.
(12) at room temperature, the 5th crude product is dissolved in anhydrous benzene, after being vented 15 minutes with nitrogen ball, sequentially adds idol Nitrogen bis-isobutyronitrile (122.7mg, 0.74mmol) and tri-n-butyl tin hydrogen (3.40mL, 12.95mmol), then tube sealing is heated to 110 DEG C, stirring about 2 hours, is then cooled to room temperature to the reaction was complete, after reaction solution is spin-dried for concentration, gained liquid silica gel Chromatography purifies, and obtains compound O, about 108mg, yield 39%.The detection data and embodiment of the compound O of the present embodiment 1 is identical, and details are not described herein.The synthetic route of compound O is as follows：
(13) at 0 DEG C, compound O (250.0mg, 0.54mmol) is dissolved in anhydrous 1,2- dichloroethanes (10mL), 2,4,6- trimethylpyridines (720 μ L, 5.4mmol), thionyl chloride (450 μ L, 2.70mmol) is added into reaction system successively And pyridine (264 μ L, 3.24mmol), and stirring about 12 minutes, is quenched to the reaction was complete with saturated sodium bicarbonate solution at 0 DEG C It goes out after reaction, with ether dilution, extraction, organic phase uses hydrochloric acid, the saturated common salt water washing of 1mol/L, uses anhydrous sodium sulfate successively It is dry, filtering.After organic solvent is spin-dried under reduced pressure, the 6th crude product containing compound P is obtained.
(14) at room temperature, the 6th crude product is dissolved in anhydrous ethylamine (5mL), be carefully added into lithium metal (19.0mg, 2.70mmol), solution turned blue after ten minutes is stirred, continues to be stirred at room temperature 30 minutes, is then cooled to -78 DEG C, is added successively Enter isoprene (1mL) and reaction is quenched in saturated ammonium chloride solution (3mL), is subsequently added into ether dilution, extraction reaction, organic phase Saturated ammonium chloride solution, the washing of saturated common salt aqueous solution is used to be dried with anhydrous sodium sulfate solid, filtering successively.Under reduced pressure will Organic solvent is spin-dried for, and gained liquid silica gel column chromatography separating purification obtains compound Q, about 72mg, yield 37%.This implementation The detection data of the compound Q of example is same as Example 1, and details are not described herein.The synthetic route of compound Q is as follows：
(15) at room temperature, compound Q (70.0mg, 194 μm of ol) is dissolved in dichloromethane (20mL), carbonic acid is added The buffer solution (pH=8.6,20mL) of hydrogen sodium and potassium carbonate, wherein in the buffer solution of carbonate, sodium bicarbonate it is mole dense Degree is 0.5mol/L, and the molar concentration of potassium carbonate is 0.05mol/L.Then the tetrabutyl is sequentially added under continuous agitation Ammonium chloride (274.4mg, 970 μm of ol), 2,2,6,6- tetramethyl piperidine oxides (30.2mg, 194 μm of ol) and N- chloros fourth two Acid imide (206.0mg, 1.55mmol) is detected with thin-layered chromatography and is reacted, and the reaction was complete about 3 hours, then uses ethyl acetate Dilution, extraction, then saturated sodium thiosulfate, saturated common salt water washing are used successively, it is dried with anhydrous sodium sulfate.Organic phase decompression is dense After contracting, residue silica gel post separation obtains compound R, 43mg, yield 63%.The detection data of the compound R of the present embodiment Same as Example 1, details are not described herein.The synthetic route of compound R is as follows：
(16) compound R (40.0mg, 0.11mmol) is dissolved in anhydrous methylene chloride (5mL), then at -78 DEG C Under, sequentially add 2,6- lutidines (47.0 μ L, 0.33mmol) and triethyl group silicon substrate triflate (54.0 μ L, 0.22mmol), after stirring 1 hour, saturated sodium bicarbonate solution is added, reaction is quenched, with ethyl acetate dilution, extract reaction solution, Organic phase is dried through saturated common salt water washing, then with anhydrous sodium sulfate, filtering, after organic phase is concentrated under reduced pressure, residue silicagel column Chromatography purifies, and obtains compound S, 40.8mg, yield 78%.The detection data of the compound S of the present embodiment and embodiment 1 Identical, details are not described herein.The synthetic route of compound S is as follows：
(17) at room temperature, compound S (40.0mg, 95.6 μm of ol) is dissolved in anhydrous tertiary butanol (5mL), is removed with argon gas Then oxygen about 10 minutes is added the tetrahydrofuran solution (a concentration of 1.8mol/L, 478 μm of ol) of the potassium tert-butoxide of 265.6 μ L, connects It and changes oxygen air blowing about 18 minutes, then reaction is quenched with saturated ammonium chloride solution, reaction solution, organic phase warp is extracted with ethyl acetate It is dried, is filtered with anhydrous sodium sulfate after saturated common salt water washing, after organic phase is concentrated under reduced pressure, the separation of residue silica gel column chromatography is pure Change, obtains compound T, 20.1mg, yield 47%.The detection data of the compound T of the present embodiment is same as Example 1, herein It repeats no more.The synthetic route of compound T is as follows：
(18) compound U (49.1mg, 271.2 μm of ol) is dissolved in anhydrous tetrahydro furan (50mL), at -78 DEG C, is added Enter the hexane solution (concentration 1.6mol/L, 271.2 μm of ol) of 169.5 μ L n-BuLis, and react 1 hour at -78 DEG C, so After anhydrous tetrahydro furan (3mL) solution of compound T (20.0mg, 45.2 μm of ol) is added dropwise the reaction was continued 1 hour, then use Reaction is quenched in methanol (182 μ L, 4.52mmol), then is warming up to room temperature, and the tetrabutyl ammonium fluoride of 904.0 μ L is added to reaction system (1.0mol/L, 904.0 μm of ol) the reaction was continued, and the reaction was complete after 2 hours for reaction, is then quenched instead with saturated ammonium chloride solution It answers, reaction solution is extracted with ethyl acetate, organic phase uses saturated ammonium chloride solution, saturated common salt aqueous solution to wash successively, and use is anhydrous Solid sodium sulfate is dried, filtering.Organic solvent is spin-dried under reduced pressure, gained liquid silica gel column chromatography obtains sterides compound Object cyclocitrinol, 11.0mg, yield 66%.The detection data of the steroidal compounds cyclocitrinol of the present embodiment with Embodiment 1 is identical, and details are not described herein.The synthetic route of steroidal compounds cyclocitrinol is as follows：
Each technical characteristic of embodiment described above can be combined arbitrarily, to keep description succinct, not to above-mentioned reality It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, it is all considered to be the range of this specification record.
Several embodiments of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection of the present invention Range.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.

Claims (10)

1. a kind of preparation method of steroidal compounds, which is characterized in that include the following steps：
Anhydrous and under conditions of -78 DEG C, it is by structural formulaCompound A and lithium diisopropylamine exist It is reacted in first organic solvent 0.5 hour~4 hours, trim,ethylchlorosilane is then added, and the reaction was continued, obtains containing structural formula ForCompound B the first crude product, wherein the compound A and the lithium diisopropylamine Molar ratio be 1:1~1:The molar ratio of 2.5, the compound A and the trim,ethylchlorosilane is 1:1~1:2, Me be first Base, TMS are trimethyl silicon substrate；
At room temperature, first crude product is reacted in a second organic solvent with 2- iodosobenzoic acids, obtains structural formula ForCompound C, wherein the molar ratio of the compound A and the 2- iodosobenzoic acids is 1:1 ~1:2.5；
Anhydrous and under conditions of 0 DEG C, the compound C is reacted 1 with azidotrimethylsilane in third organic solvent Hour~5 hours, iodine and pyridine is then added, and the reaction was continued at room temperature 10 hours~14 hours, obtaining structural formula isCompound D, wherein the molar ratio of the compound C and the azidotrimethylsilane is 1: 1~1:The molar ratio of 5, the compound C and the pyridine is 1:5~1:10, the molar ratio of the compound C and the iodine is 1:1~1:5；
In room temperature and the atmosphere of protective gas, cuprous, lithium acetate, catalyst and knot by the compound D and thiophene -2-carboxylic acid Structure formula isCompound E reacted in the 4th organic solvent, obtaining structural formula isCompound F, wherein the compound D and the thiophene -2-carboxylic acid are cuprous Molar ratio is 1:1~1:The molar ratio of 1.5, the compound D and the lithium acetate is 1:2~1:4, the compound D and institute The molar ratio for stating compound E is 1:1~1:2, TBS be t-Butyldimethylsilyl,nBu is normal-butyl；
The compound F, Nickel Chloride and sodium borohydride are mixed in the 5th organic solvent at -78 DEG C, until reactant System is warming up to room temperature from -78 DEG C, and obtaining structural formula isCompound G, wherein institute The molar ratio for stating compound F and the Nickel Chloride is 1:3~1:8, the molar ratio of the compound F and the sodium borohydride is 1:5~1:15；
Anhydrous and under conditions of -78 DEG C, it is by structural formulaCompound H, tert-butyl lithium it is anti-in the 6th organic solvent It answers 0.5 hour~1 hour, the compound G is then added, and the reaction was continued, and obtaining structural formula is Compound I, wherein the molar ratio of the compound G and the compound H are 1:2~1:4, the compound G and the uncle The molar ratio of butyl lithium is 1:3~1:6, TIPS be triisopropylsilyl；
At room temperature, the compound I and tetrabutyl ammonium fluoride are reacted 0.5 hour~2 hours in the 7th organic solvent, so Water, sodium acetate, sodium bicarbonate and N- bromo-succinimides is added under conditions of 0 DEG C afterwards, and is reacted under conditions of 0 DEG C 0.5 hour~1 hour, obtain be containing structural formulaCompound J the second crude product, Wherein, the molar ratio of the compound I and the tetrabutyl ammonium fluoride is 1:2.5~1:4, the compound I and the acetic acid The molar ratio of sodium is 1:1~1:The molar ratio of 3, the compound I and the sodium bicarbonate is 1:1~1:3, the compound I Molar ratio with the N- bromo-succinimides is 1:1~1:2；
Anhydrous and at room temperature, by second crude product, 4-dimethylaminopyridine, 2,2,6,6- tetramethyl piperidines and acetic anhydride Reacted in the 8th organic solvent, obtain be containing structural formulaCompound K third it is thick Product, wherein the molar ratio of the compound I and the 4-dimethylaminopyridine is 1:0.1~1:1, the compound I and institute The molar ratio for stating 2,2,6,6- tetramethyl piperidines is 1:2~1:4, the molar ratio of the compound I and the acetic anhydride is 1:2~1:4, Ac be acetyl group；
In anhydrous conditions, by the third crude product and 2,2,6,6- tetramethyl piperidines are in the 9th organic solvent in 145 DEG C It is reacted at~160 DEG C, obtaining structural formula isCompound L, wherein the compound I with The molar ratio of the 2,2,6,6- tetramethyl piperidines is 1:1.5~1:4；
Under conditions of 0 DEG C, the compound L is reacted with sodium borohydride in the mixed liquor of tetrahydrofuran and water, is contained There is the structural formula to beCompound M the 4th crude product, wherein the compound L and institute The molar ratio for stating sodium borohydride is 1:1~1:3；
It is anhydrous and under conditions of -78 DEG C, the 4th crude product and bis- (trimethylsilyl) potassamides is organic the tenth It is reacted in solvent 0.1 hour~1 hour, carbon disulfide and iodomethane is then added, the reaction was continued 1 hour~2 hours, is contained There is the structural formula to beCompound N the 5th crude product, wherein the compound L with The molar ratio of bis- (trimethylsilyl) potassamides is 1:1~1:1.5, the compound L rubs with the carbon disulfide You are than being 1:2~1:8, the molar ratio of the compound L and the iodomethane is 1:2~1:8；
Under 80 DEG C~110 DEG C atmosphere with protective gas, by the 5th crude product, azodiisobutyronitrile and tri-n-butyl tin Change hydrogen to react in the 11st organic solvent, obtaining structural formula isCompound O, wherein institute The molar ratio for stating compound L and the azodiisobutyronitrile is 1:0.1~1:0.4, the compound L and the tri-n-butyl tin The molar ratio for changing hydrogen is 1:4~1:10；
It is under conditions of 0 DEG C, the compound O, 2,4,6- trimethylpyridines, thionyl chloride and pyridine is organic molten the 12nd Reacted in agent, obtain be containing structural formulaCompound P the 6th crude product, wherein it is described The molar ratio of compound O and the 2,4,6- trimethylpyridines is 1:5~1:10, the compound O and the thionyl chloride Molar ratio is 1:2~1:The molar ratio of 5, the compound O and the pyridine is 1:4~1:6；
Anhydrous and at room temperature, the 6th crude product and lithium are reacted in ethamine, obtaining structural formula is Compound Q, wherein the molar ratio of the compound O and the lithium is 1:5~1:20；
At room temperature, by the compound Q, tetrabutylammonium chloride, 2,2,6,6- tetramethyl piperidine oxides and N- chloros fourth two Acid imide reacts in the mixed solution of the 13rd organic solvent and carbonate buffer solution, obtains structural formula and isCompound R, wherein the molar ratio of the compound Q and the tetrabutylammonium chloride is 1: 2~1:5, the molar ratio of the compound Q and described 2,2,6,6- tetramethyl piperidine oxides is 1:0.2~1:1, the chemical combination The molar ratio of object Q and the N- chlorosuccinimides is 1:2~1:8；
Anhydrous and under conditions of -78 DEG C, by the compound R, 2,6- lutidines and triethyl group silicon substrate trifluoromethanesulfonic acid Ester reacts in the 14th organic solvent, obtains structural formula and isCompound S, wherein institute The molar ratio for stating compound R and the 2,6- lutidines is 1:3~1:6, the compound R and the triethyl group silicon substrate three The molar ratio of fluorine methanesulfonates is 1:2~1:4, TES be triethyl group silicon substrate；
At room temperature, the compound S and potassium tert-butoxide are carried out in the 15th organic solvent under anhydrous and oxygen-free environment pulling out hydrogen Reaction, then reacts 0.1 hour~0.3 hour under aerobic environment, obtaining structural formula is's Compound T, wherein the molar ratio of the compound S and the potassium tert-butoxide is 1:2~1:5；
Anhydrous and under conditions of -78 DEG C, it is by structural formulaCompound U and n-BuLi have the 16th It is reacted 0.5 hour~1 hour in solvent, the compound T is then added, the reaction was continued 0.1 hour~1 hour, then uses first Reaction is quenched in alcohol, obtains reaction solution, then at room temperature, tetrabutyl ammonium fluoride is added in the reaction solution, and react 1 hour ~2 hours, obtaining structural formula wasSteroidal compounds, wherein the compound T Molar ratio with the compound U is 1:4~1:The molar ratio of 8, the compound T and the n-BuLi is 1:3~1:6, The molar ratio of the compound T and the tetrabutyl ammonium fluoride is 1:12~1:20, X are selected fromnBu3One kind in Sn and I.
2. the preparation method of steroidal compounds according to claim 1, which is characterized in that described and then addition trimethyl chlorine It is whether complete using thin-layered chromatography detection reaction in silane the step of the reaction was continued.
3. the preparation method of steroidal compounds according to claim 1, which is characterized in that first organic solvent is nothing Water tetrahydrofuran or anhydrous ether.
4. the preparation method of steroidal compounds according to claim 1, which is characterized in that second organic solvent is two First sulfoxide or N,N-dimethylformamide.
5. the preparation method of steroidal compounds according to claim 1, which is characterized in that described in anhydrous and 0 DEG C item Under part, the compound C is reacted 1 hour~5 hours with azidotrimethylsilane in third organic solvent, is then added Iodine and pyridine, and the step of the reaction was continued at room temperature 10~14 hours is specially：In anhydrous conditions, by the compound C It is dissolved in the third organic solvent, obtains the third organic solution of compound C；The iodine is dissolved in the pyridine, Obtain the pyridine solution of iodine；Under conditions of 0 DEG C, the third that the compound C is added in the azidotrimethylsilane is had In machine solution, reacts 1 hour~5 hours, the pyridine solution of the iodine is then added, is then warming up to room temperature, the reaction was continued 10 Hour~14 hours.
6. the preparation method of steroidal compounds according to claim 1, which is characterized in that the 6th organic solvent is by nothing Water ether and anhydrous pentane composition；
It is described anhydrous and under conditions of -78 DEG C, be by structural formulaCompound H, tert-butyl lithium has the 6th It is reacted 0.5 hour~1 hour in solvent, the compound G is then added is specially the step of the reaction was continued：At -78 DEG C Under the conditions of, the compound H is dissolved in the anhydrous ether, the diethyl ether solution of compound H is formed；By the nothing of tert-butyl lithium Water pentane solution, which is added in the diethyl ether solution of the compound H, to react 0.5 hour~1 hour, and the nothing of compound G is then added Water diethyl ether solution, the reaction was continued.
7. the preparation method of steroidal compounds according to claim 1, which is characterized in that the 15th organic solvent by Anhydrous tertiary butanol and anhydrous tetrahydro furan composition；
It is described at room temperature, by the compound S and potassium tert-butoxide in the 15th organic solvent under anhydrous and oxygen-free environment into Row pull out hydrogen reaction the step of be specially：At room temperature, the compound S is dissolved in the anhydrous tertiary butanol, obtains chemical combination The anhydrous tertiary butanol solution of object S；Then in the absence of oxygen, uncle is added in the anhydrous tertiary butanol solution of the compound S The anhydrous tetrahydrofuran solution of butanol potassium pulls out hydrogen reaction described in carrying out.
8. the preparation method of steroidal compounds according to claim 1, which is characterized in that the 16th organic solvent by Anhydrous tetrahydro furan and anhydrous n-hexane composition；
It is described anhydrous and under conditions of -78 DEG C, be by structural formulaCompound U and n-BuLi the tenth It is reacted 0.5 hour~1 hour in six organic solvents, the compound T is then added, 0.1 hour~1 hour step that the reaction was continued It is rapid to be specially：The compound U is dissolved in anhydrous tetrahydro furan, n-BuLi is then added under conditions of -78 DEG C Anhydrous n-hexane solution, and reacted 0.5 hour~1 hour at -78 DEG C, the anhydrous tetrahydro furan for being subsequently added into compound T is molten Liquid, the reaction was continued 0.1 hour~1 hour.
9. the preparation method of steroidal compounds according to claim 1, which is characterized in that described by the 6th crude product and lithium The step of reaction, is specially in ethamine：At room temperature, the 6th crude product is dissolved in the anhydrous ethylamine, is then added Enter the lithium, after reacting 0.5 hour~1 hour, is cooled to -78 DEG C, is quenched successively with isoprene and saturated ammonium chloride solution Reaction.
10. the preparation method of steroidal compounds according to claim 1, which is characterized in that the carbonate buffer solution is The mixed aqueous solution of sodium bicarbonate and potassium carbonate.
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CN110330544A (en) * 2019-06-05 2019-10-15 宁波大学 A kind of bicyclic steroid of 4,4,1- and its preparation method and application
CN110330544B (en) * 2019-06-05 2021-07-13 宁波大学 4,4, 1-bicyclic steroid compound and preparation method and application thereof

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