CN108164461A - A kind of fully synthetic and enantiomter the method for splitting of natural products (±)-Cananga odorata alkali - Google Patents
A kind of fully synthetic and enantiomter the method for splitting of natural products (±)-Cananga odorata alkali Download PDFInfo
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract
The invention discloses a kind of fully synthetic and its enantiomter chiral separation methods of natural products (±) Cananga odorata alkali, belong to technical field of organic synthesis.Natural products (±) Cananga odorata alkali in this method is to be reacted in natural products (±) atisine G for substrate by tetrahydrofuran/lithium methide, obtain natural products (±) Cananga odorata alkali and its enantiomter, again with chiral semipreparative high performance liquid chromatography instrument, carry out the fractionation of corresponding isomers, and Cananga odorata alkali and its corresponding isomers are obtained, gross production rate 17.9%, this invention simplifies synthetic methods, improve fully synthetic gross production rate, and Structural Identification is carried out to it, not only solve the disagreement in Cananga odorata alkali specific rotatory power, it also provides the foundation for the further research of such compound and powerful guarantee.
Description
Technical field
The present invention relates to organic synthesis technology and separation technology field more particularly to a kind of natural products (±)-Cananga odoratas
Fully synthetic and enantiomter the method for splitting of alkali.
Background technology
Cananga odorata (Cananga odorata) belongs to the evergreen megaphanerophyte of Annonaceae, the woody spice berry in the torrid zone.Divide extensively
Being distributed in the ground such as each torrid areas in the world, domestic Guangdong, Guangxi, Fujian, Sichuan, Yunnan, Taiwan has cultivation.Cananga odorata is mainly with new
Fresh flower valve carrys out steam oil, claims Java Cananga Oil.Fresh flower oil yield is up to 2~3%.It is mainly used for the diseases such as skin tinea, malaria, influenza in the traditional Chinese medical science
Treatment.2001, the Wu Yongchang seminars of Kao-hsiung medical university were isolated to Cananga odorata alkali for the first time from Cananga odorata.From
It is seen in structure, there are one pyridine rings for the compound of the type, and the heptatomic ring of a saturation, there are two chiral centres for tool, are typical
Epiguaipyridine Alkaloid.The more wound pyridine compounds and their contained in natural products generally all there is special physiology to live
Property.Therefore, which results in numerous synthesis chemists, the great interest of biological family and virologist.2008, the Chinese Academy of Sciences
Xinjiang physiochemical techniques research institute A Jiaike Baeyer Ai Sa researchers seminar is isolated to five from Artemisia rupestris for the first time
The more wound pyridine type sesquiterpenoids alkaloid of a structure novel.2012, He Fei of the seminar etc. from Artemisia rupestris again
The compound of isolated eight the type.(and compound 14 is named as atisine (Rupestine) }.
According to the literature, there is liver cancer cells toxicity as typical epiguaipyridine Alkaloid-Cananga odorata alkali.2006
Year, Gavin D.Henry complete the fully synthetic of the compound for the first time.
Gavin seminars have obtained midbody compound G-7 by six step gross production rate 20.52% of raw material of citronellene first,
2- methylene -1,3-PD obtains another midbody compound G-11, then with intermediate for three step gross production rate 36% of raw material
G-7 is reacted with intermediate G-11 obtains Cananga odorata alkali by eight steps reaction gross production rate 6%.The method of Gavin seminars is not only numerous
It is trivial, low yield, the reagents such as KCN severe toxicity used in reaction；Moreover, the Cananga odorata alkali { [α] that they synthesizeD 21=+17.9 (c=
1.34,CHCl3) with Wu Yongchang seminars discrete obtained compound { [α]D 25=-76.2 (c=0.06, CHCl3) optical value
Symbol is opposite.For the explanation given by this phenomenon Gavin seminars be sample concentration it is bigger it is measured come optical value more
Reliably, it is impossible to convincing.
James Vyvyan in 2017 have also attempted the synthesis of synthesis Cananga odorata alkali and its isomers.
Although Vyvyan seminars achievement has synthesized Cananga odorata alkali and its isomers, not only their reaction conditions are severe
It carves, low yield, and to Cananga odorata alkali, its isomers is not split, Gavin seminars and Wu Yongchang subjects before solution
Disagreement on the obtained Cananga odorata alkali optical value of group.Up to now, other than above-mentioned two seminar, have no other people or
Unit reports the fully synthetic research of the compound, in view of natural product chemistry man (Wu Yongchang) and synthetic organic chemist (Gavin
D.Henry) the disagreement in Cananga odorata alkali physical constant specific rotatory power, the present invention are the denominations of invention 201710407508.7
Further to be ground on the basis of fully synthetic and its enantiomter the method for splitting of kind of a natural products (±)-atisine G
Study carefully, the reaction method before not only improving, and successfully obtained Cananga odorata alkali and its corresponding isomers, gross production rate
17.9%, synthetic method is simplified, improves fully synthetic gross production rate, the further research for such compound, which has provided, tries hard to keep
Barrier.
Bibliography
1.Tian-Jye Hsieh；Fang-Rong Chang；Yi-Chen Chia；Chung-Yi Chen；Hui-Fen
Chiu；Wu,Y.-C.,Cytotoxic Constituents of the Fruits of Cananga
odorata.J.Nat.Prod.2001,64,616-619.
2.Koyama,J.；Okatani,T.；Tagahara,K.；Suzuta,V.,Synthesis of
guaipyridine,epiguaipyridine and related compounds.Heterocycles 1987,26(4),
926-927.
3.Su,Z.；Wu,H.；Yang,Y.；Aisa,H.A.；Slukhan,U.；Aripova,S.,Preparative
isolation of guaipyridine sesquiterpene alkaloid from Artemisia rupestris
L.flowers using high-speed counter-current chromatography.J.Sep.Sci.2008,31
(12),2161-6.4.Su,Z.；Wu,H.；Yang,Y.；Aisa,H.A.；Slukhan,U.；Aripova,S.,New
Guaipyridine Sesquiterpene Alkaloids from Artemisia rupestris
L.Helv.Chim.Acta 2010,93,33-38.5.He,F.；Nugroho,A.E.；Wong,C.P.；Hirasawa,Y.；
Shirota,O.；Morita,H.；Aisa,H.A.,Rupestines F—M,New Guaipyridine Sesquiterpene
Alkaloids from Artemisia rupestris.Chem.Pharm.Bull.2012,60(2),213-218.
6.Craig,D.；Henry,G.D.,Total Synthesis of the Cytotoxic Guaipyridine
Sesquiterpene Alkaloid(+)-Cananodine.Eur.J.Org.Chem.2006,16,3558-3561.
7.Patrick Shelton,Toby J.Ligon,Jennifer M.Dell(née Meyer),Loagan
Yarbrough,James R.Vyvyan,Synthesis of cananodine by intramolecular epoxide
opening.Tetrahedron Letters,2017,58,3478-3481.
The present invention is at home and abroad in relation to the invention of patent, the comprehensive analysis of document and this seminar《A kind of natural products
Fully synthetic and its enantiomter the method for splitting of (±)-atisine G》(number of patent application：201710407508.7)
On the basis of, using 2- methyl -5- bromopyridines as raw material, a series of methodology of organic synthesis before improveing successfully has obtained a kind of day
Separation splits and obtains its enantiomter while right product (±)-Cananga odorata alkali.
Invention content
The object of the present invention is to provide a kind of the fully synthetic and enantiomter of natural products (±)-Cananga odorata alkali
Method for splitting, and its absolute configuration is determined.Natural products (±)-Cananga odorata alkali in this method is in natural products
(±)-atisine G is reacted for substrate by tetrahydrofuran/lithium methide, obtains (±)-Cananga odorata alkali and its enantiomter,
Again with chiral semipreparative high performance liquid chromatography instrument, carry out the fractionation of corresponding isomers, and successfully obtained Cananga odorata alkali and
It corresponds to isomers, and gross production rate 17.9%, this invention simplifies synthetic methods, improve fully synthetic gross production rate, and it is carried out
Structural Identification not only solves the disagreement in Cananga odorata alkali specific rotatory power, is also provided for the further research of such compound
Basis and powerful guarantee.
A kind of fully synthetic and enantiomter the method for splitting of natural products (±)-Cananga odorata alkali of the present invention,
Natural products (±)-Cananga odorata alkali in this method be using natural products (±)-atisine G as substrate by tetrahydrofuran/
Lithium methide reacts, and obtains (±)-Cananga odorata alkali and its enantiomter, then with chirality semipreparative high performance liquid chromatography instrument, into
The fractionation of the corresponding isomers of row, structural formula are：
Wherein：
Compound 1 is 5- bromine 2- picolines；
Compound 2 is N- oxygen -5- bromine 2- picolines；
Compound 3 is 6- cyano -5- bromine 2- picolines；
Compound 4 is 3- (the bromo- 6- picolines of 3-) -3- carbonyl propionic acid methyl esters；
Compound 5 is 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters；
Compound 6 is 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- amylene-4 acid methyl esters；
Compound 7 is 2,5- dimethyl -5- alkene -9- oxos-cycloheptane simultaneously [b] pyridine -8- methyl formates；
Compound 8 is 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane simultaneously [b] pyridine -8- methyl formates；
Compound 9 is 2,5- dimethyl -5,8- diene-cycloheptane simultaneously [b] pyridine -8- methyl formates；
Compound 10 is (5- methyl -8- methyl formates)-cycloheptane simultaneously [b] pyridine -2- methyl/{ (±)-atisine
G}；
Compound 11 for { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane simultaneously [b] pyridine -2- methyl/(±)-according to
Blue perfume alkali }；
Compound 12 is Cananga odorata alkali；
Compound 13 is (5S, 8S)-Cananga odorata alkali；
Concrete operations follow these steps to carry out：
A, compound 1 is dissolved in for 5- bromine 2- picolines 2.0g in dichloromethane solution, system is placed under ice bath in batches
After adding in 85% metachloroperbenzoic acid 2.9g of purity, room temperature is warmed naturally to, is stirred overnight reaction, it after reaction will reaction
Liquid is poured into the sodium sulfite solution of saturation and is quenched, and stirring is extracted 3 times after 1 hour with dichloromethane, merges organic phase, with nothing
Water magnesium sulfate is dried, and nitrogen oxidation product Compound 2 is obtained as the bromo- 2- methyl-N- oxy picolinates of 5- after removing organic solvent；
B, under nitrogen protection, compound 2 is dissolved in for the bromo- 2- methyl-N- oxy picolinates 1.0g of 5- in acetonitrile solution, according to
Secondary addition trimethylsilyl cyanide 2.1g and triethylamine 2.2ml after flowing back 12 hours, removes organic solvent, and purifying obtains compound
3 be the bromo- 6- methyl -2- cyanopyridines of 3-；
C, under vacuum state, mass ratio 40 will be contained:60 crystallization water:Zinc chloride 7.2g-8.0g is heated to melting water removal,
Under nitrogen protection, 1,2- dichloroethanes is sequentially added, compound 3 is the bromo- 6- methyl -2- cyanopyridines 5.5g of 3-, malonic acid list
Methyl esters sylvite 11g-13g and diisopropylethylamine 1.5g-1.8g is stirred at reflux 12-16 hours, is added after system is cooled to room temperature
Enter 6N hydrochloric acid, flow back 1 hour again, separate organic phase, water phase is extracted 3 times with dichloromethane, with anhydrous sulphur after merging organic phase
Sour magnesium drying, removes organic solvent, and purifying obtains compound 4 as 3- (the bromo- 6- picolines of 3-) -3- carbonyl propionic acid methyl esters；
D, compound 4 is dissolved in for 3- (the bromo- 6- picolines of 3-) -3- carbonyl propionic acid methyl esters 1.0g in absolute ethyl alcohol,
Sodium ethoxide 0.6g-1.0g is added in ice bath, 3- bromopropene 0.7ml-1.0ml are added in while stirring, ambient temperature overnight reaction removes
Organic solvent, column chromatography purifying obtain compound 5 as 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters；
E, compound 5 is dissolved in dioxy for 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters 1.0g
In the mixed solution of six rings and water, tetra-triphenylphosphine palladium catalyst 0.4g-0.8g, sodium carbonate 1g-1.5g, isopropenyl boron are added in
Sour pinacol ester 0.71ml-1.0ml, agitating and heating flow back 3-5 hours, and solvent, column chromatography are removed after system is cooled to room temperature
Purifying obtains compound 6 as 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- amylene-4 acid methyl esters；
F, under nitrogen protection, it is 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- penetenoic acids by compound 6
Methyl esters 1.0g is dissolved in dichloromethane solution, adds in Grubbs bis- generations catalyst 0.3g-0.5g, heating reflux reaction 12-16
Hour, the system for the treatment of is cooled to room temperature, and removes organic solvent, and column chromatography obtains compound 7 as 2,5- dimethyl -5- alkene -9- oxygen
Generation-cycloheptane simultaneously [b] pyridine -8- methyl formates；
G, it is 2,5- dimethyl -5- alkene -9- oxos-cycloheptane simultaneously [b] pyridine -8- formic acid first by compound 7 under ice bath
Ester 100mg is dissolved in absolute methanol, adds in sodium borohydride 15mg-30mg, warms naturally to room temperature, after reacting 3-5 hours, is added
Water quenching is gone out reaction, removes solvent, column chromatography, and purifying obtains compound 8 as 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane simultaneously
[b] pyridine -8- methyl formates；
H, by compound 8, for 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane, simultaneously [b] pyridine -8- methyl formates 100mg is molten
In pyridine, temperature 60 C is heated to, adds methylsufonyl chloride 45mg-60mg, after reacting 3-5 hours, is cooled to room temperature, adds
Water quenching is gone out reaction, then separates organic phase with dichloromethane extraction, and organic phase is dried with anhydrous magnesium sulfate, and column chromatography purifying obtains
Compound 9 is 2,5- dimethyl -5,8- diene-cycloheptane simultaneously [b] pyridine -8- methyl formates；
I, by compound 9, for 2,5- dimethyl -5,8- diene-cycloheptane, simultaneously [b] pyridine -8- methyl formates 50mg is dissolved in nothing
In water methanol, palladium-carbon catalyst 15mg-20mg is added under ice bath, is passed through hydrogen, be stirred overnight at room temperature reaction, removes solvent, uses
Thin layer chromatography method isolates and purifies, and it is (5- methyl -8- methyl formates)-cycloheptane simultaneously [b] pyridine -2- to obtain compound 10
Methyl；
J, by compound 10, for (5- methyl -8- methyl formates)-cycloheptane, simultaneously [b] pyridine -2- methyl 50mg is dissolved in drying
Tetrahydrofuran in, by system as at -10 DEG C of temperature, add in 3-5 times of lithium methide, after 1 hour of reaction, water quenching added to go out instead
Should, then extracted 3 times with dichloromethane, merge organic phase, after being dried with anhydrous magnesium sulfate, cross filter solid, filtrate removes solvent and obtains
It is { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane simultaneously [b] pyridine -2- methyl to compound 11；
K, by compound 11, for { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane, simultaneously [b] pyridine -2- methyl uses half
Preparative high performance liquid chromatography is split, and it be Cananga odorata alkali and compound 13 for (5S, 8S)-Cananga odorata alkali to obtain compound 12.
A kind of fully synthetic and enantiomter the method for splitting of natural products (±)-Cananga odorata alkali of the present invention,
This method be application this seminar early period a kind of natural products (±) of patent of invention-atisine G it is fully synthetic and its right
Reflect the method for splitting of isomers, number of patent application：Equally with 2- methyl -5- bromopyridines (1) on the basis of 201710407508.7
For raw material, aoxidize to obtain nitrogen oxidation product Compound (2) by metachloroperbenzoic acid, by compound (2) through Reissert-
Henze reaction cyano replace to obtain compound (3), wherein both except that：The present invention is by obtained compound (3) and third
'beta '-ketoester (4) is obtained by the reaction by decarboxylation Blaise in acid monoethyl ester sylvite, and compound (4) is alkylated under the conditions of sodium ethoxide
Compound (5) is obtained, further Suzuki coupling reactions obtain compound (6), and compound (6) is molecule internal olefin subdivision occur
Key intermediate compound (7) is obtained by the reaction in solution, and compound (7) obtains compound (8), final compound with sodium borohydride reduction
(8) it is eliminated under the conditions of pyridine/methylsufonyl chloride and obtains compound (9), compound (9) is dissolved in methanol and passes through palladium carbon
Catalytic hydrogenation obtains compound (10), and in tetrahydrofuran is dissolved in, system is placed at -10 DEG C of temperature and methyl is added dropwise compound (10)
Obtain compound (11) after lithium, then by compound (11) with SHIMADZU LC20A Semi-preparative High Performance liquid phases CHIRALPAK
ID (Lot No.ID00CE-QI011) is split, respectively obtain compound (12) Cananga odorata alkali and compound (13) (5S, 8S)-according to
Blue perfume alkali.
A kind of fully synthetic and enantiomter the method for splitting of natural products (±)-Cananga odorata alkali of the present invention,
The synthetic route of this method is as follows：
Description of the drawings
Fig. 1 is the high resolution mass spectrum figure of the compounds of this invention (13)；
Fig. 2 is the high resolution mass spectrum figure of natural products Cananga odorata alkali of the present invention；
Fig. 3 is the optical value figure of the compounds of this invention (13)；
Fig. 4 is the optical value figure of natural products Cananga odorata alkali of the present invention；
Fig. 5 is the experiment ECD of the compounds of this invention (13) and Cananga odorata alkali and calculates ECD spectrums, and wherein curve A is compound
(13) experiment ECD curves；Curve B is the experiment ECD curves of Cananga odorata alkali；Curve C is the calculating ECD curves of Cananga odorata alkali；
Specific embodiment
In order to make the present invention clearer, with reference to embodiments, the present invention will be described in further detail, should manage
Solution, described embodiment are only used for explaining the present invention, do not limit the present invention.
Embodiment 1
A, compound 1 is dissolved in dichloromethane solution 30ml for 5- bromine 2- picolines 2.0g (12mmol), system is placed in
Room temperature is warmed naturally to after the metachloroperbenzoic acid 2.9g (13.9mmol) that purity is 85% is added portionwise under ice bath, it is stirred
Night reacts, and is poured into reaction solution in the sodium sulfite solution of saturation is quenched after reaction, stirs 1 hour and uses dichloro later
Methane 150ml is extracted 3 times, is merged organic phase, is dried with anhydrous magnesium sulfate, and nitrogen oxidation product chemical combination is obtained after removing organic solvent
Object 2 be the bromo- 2- methyl-N- oxy picolinates of 5-, yield 93%, 2.0g；
B, under nitrogen protection, by compound 2, for the bromo- 2- methyl-N- oxy picolinates 1.0g (5.4mmol) of 5-, to be dissolved in acetonitrile molten
In liquid 20ml, trimethylsilyl cyanide 2.1g (21.6mmol) and triethylamine 2.2ml (16.2mmol) are sequentially added, is flowed back 12 hours
Afterwards, organic solvent is removed, it is COMBIFLASH that standby chromatography is suppressed in, mobile phase：Volume ratio 1:10 ethyl acetate:Petroleum ether
Purifying obtains compound 3 as the bromo- 6- methyl -2- cyanopyridines of 3-, yield 85%, 0.9g；
1H NMR (400MHz, Chloroform-d) δ 7.98 (d, J=8.2Hz, 1H), 7.24 (d, J=3.0Hz, 1H),
2.57(s,3H)；
C, under vacuum state, it is 40 that will contain mass ratio:60 crystallization water:Zinc chloride 7.2 (32.5mmol) is heated to melting
Water removal under nitrogen protection, sequentially adds 1,2- dichloroethanes 75ml, compound 3 is the bromo- 6- methyl -2- cyanopyridines of 3-
5.5g (27.9mmol), malonic acid monomethyl ester sylvite 11g (65mmol) and diisopropylethylamine 1.5ml (9.1mmol), are stirred back
Stream 12 hours, etc. systems be cooled to room temperature after add in 6N hydrochloric acid 20ml, again flow back 1 hour, separate organic phase, water phase dichloro
Methane extracts 3 times, is dried after merging organic phase with anhydrous magnesium sulfate, removes organic solvent, and purifying obtains compound 4 as 3- (3-
Bromo- 6- picolines) -3- carbonyl propionic acid methyl esters, yield 75%, 6.0g；
D, compound 4 is dissolved in for 3- (the bromo- 6- picolines of 3-) -3- carbonyl propionic acid methyl esters 1g (3.5mmol) anhydrous
In ethyl alcohol 10ml, sodium ethoxide 0.6g (3.9mmol) is added in ice bath, 3- bromopropenes 0.7ml is added in while stirring
(3.9mmol), ambient temperature overnight reaction after reaction terminates, remove organic solvent, column chromatography (mobile phase：Volume ratio 1:10 second
Acetoacetic ester:Petroleum ether) purifying, compound 5 is obtained as 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters, production
Rate 80%, 0.9g；
E, compound 5 is dissolved in for 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters 1g (3.1mmol)
Volume ratio 3:1 dioxane:In the mixed solution of water, tetra-triphenylphosphine palladium catalyst 0.4g (0.3mmol), sodium carbonate are added in
1g (9.3mmol) and isopropenyl pinacol borate 0.71ml (3.3mmol), agitating and heating flow back 3 hours, treat that system cools down
Solvent, column chromatography (mobile phase are removed after to room temperature：Volume ratio 1:10 ethyl acetate:Petroleum ether) purifying, obtaining compound 6 is
2- (3- isopropenyl -6- picoline -2- formoxyls) -4- amylene-4 acid methyl esters, yield 85%, 0.7g；
F, under nitrogen protection, it is 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- penetenoic acids by compound 6
Methyl esters 1g (3.5mmol) is dissolved in dry methylene chloride solution 30ml, adds in Grubbs bis- generations catalyst 0.3g (0.3mmol),
Heating reflux reaction 12 hours, after reaction, the system for the treatment of is cooled to room temperature, and removes organic solvent, column chromatography (mobile phase：Body
Product ratio 1:5 ethyl acetate:Petroleum ether), it is 2,5- dimethyl -5- alkene -9- oxos-cycloheptane simultaneously [b] pyrrole to obtain compound 7
Pyridine -8- methyl formates, yield 42%, 0.4g；
G, it is 2,5- dimethyl -5- alkene -9- oxos-cycloheptane simultaneously [b] pyridine -8- formic acid first by compound 7 under ice bath
Ester 100mg (0.4mmol) is dissolved in absolute methanol 5ml, adds in sodium borohydride 15mg (0.4mmol), system warms naturally to room
Temperature after reaction 3 hours, adds water quenching to go out reaction, removing solvent, column chromatography (mobile phase：Volume ratio 1:3 ethyl acetate:Oil
Ether) purifying, compound 8 is obtained as 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane simultaneously [b] pyridine -8- methyl formates, yield
71%, 72mg；
H, it is 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane simultaneously [b] pyridine -8- methyl formates 100mg by compound 8
(0.4mmol) is dissolved in pyridine 10ml, is added in methylsufonyl chloride 45mg (0.4mmol) after being heated to temperature 60 C, is reacted 3 hours
Afterwards, it is cooled to room temperature, water quenching is added to go out reaction, then organic phase, organic phase anhydrous magnesium sulfate are separated with dichloromethane 30ml extractions
It is dry, column chromatography (mobile phase：Volume ratio 1:5 ethyl acetate:Petroleum ether) purifying, compound 9 is obtained as 2,5- dimethyl -5,
8- diene-cycloheptane simultaneously [b] pyridine -8- methyl formates, yield 78%, 75mg；
I, it is 2,5- dimethyl -5,8- diene-cycloheptane simultaneously [b] pyridine -8- methyl formates 50mg by compound 9
(0.2mmol) is dissolved in absolute methanol 10ml, and a concentration of 0.5% palladium-carbon catalyst 15mg is added under ice bath, is passed through hydrogen, room temperature
Reaction is stirred overnight, removes solvent after reaction, (solvent is isolated and purified with thin layer chromatography method：Volume ratio 1:5
Ethyl acetate:Petroleum ether), it is (5- methyl -8- methyl formates)-cycloheptane simultaneously [b] pyridine -2- first to respectively obtain compound 10
Base, yield 78%, 39mg；
J, by compound 10 (5- methyl -8- methyl formates)-cycloheptane, simultaneously [b] pyridine -2- methyl 50mg (0.2mmol) is molten
In anhydrous tetrahydro furan, 3 times of lithium methide (0.6mmol) is added in, reaction adds 1ml water after terminating, 3ml is used after reaction is quenched
× 3 extractions, column chromatography (mobile phase after being dried with anhydrous magnesium sulfate：Volume ratio 1:1 ethyl acetate:Petroleum ether) purifying, it obtains
It is { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane simultaneously [b] pyridine -2- methyl to compound 11, yield 88%, 44mg.
K, by compound 11, for { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane, simultaneously [b] pyridine -2- methyl uses half
Preparative high performance liquid chromatography (SHIMADZU LC-20A), hand-type column CHIRALPAK ID (Lot No.ID00CE-QI011) are torn open
Point, enantiomter (mobile phase：Volume ratio 98:2 n-hexane:Ethyl alcohol), compound 12 is obtained as Cananga odorata alkali；Compound 13
For (5S, 8S)-Cananga odorata alkali.
Embodiment 2
A, compound 15- bromine 2- picolines 2.0g (12mmol) are dissolved in dichloromethane solution 30ml, system is placed in ice
Room temperature is warmed naturally to after the metachloroperbenzoic acid 2.9g (13.9mmol) that purity is 85% is added portionwise under bath, is stirred overnight
Reaction solution, is poured into the sodium sulfite solution of saturation is quenched after reaction by reaction, stirs 1 hour and uses dichloromethane later
Alkane 150ml is extracted 3 times, is merged organic phase, is dried with anhydrous magnesium sulfate, and nitrogen oxidation product Compound is obtained after removing organic solvent
2 be the bromo- 2- methyl-N- oxy picolinates of 5-, yield 93%, 2.0g；
B, under nitrogen protection, by compound 2, for the bromo- 2- methyl-N- oxy picolinates 1.0g (5.4mmol) of 5-, to be dissolved in acetonitrile molten
In liquid 20ml, trimethylsilyl cyanide 2.1g (21.6mmol) and triethylamine 2.2ml (16.2mmol) are sequentially added, is flowed back 12 hours
Afterwards, organic solvent is removed, it is COMBIFLASH that standby chromatography is suppressed in, mobile phase：Volume ratio 1:10 ethyl acetate:Petroleum ether
Purifying obtains compound 3 as the bromo- 6- methyl -2- cyanopyridines of 3-, yield 85%, 0.9g；
1H NMR (400MHz, Chloroform-d) δ 7.98 (d, J=8.2Hz, 1H), 7.24 (d, J=3.0Hz, 1H),
2.57(s,3H)；
C, under vacuum state, it is 40 that will contain mass ratio:60 crystallizations water:Zinc chloride 7.5 (33.9mmol) is heated to melting and removes
Water under nitrogen protection, sequentially adds 1,2- dichloroethanes 75ml, compound 3 is the bromo- 6- methyl -2- cyanopyridines 5.5g of 3-
(27.9mmol), malonic acid monomethyl ester sylvite 12g (70.9mmol) and diisopropylethylamine 1.6ml (9.8mmol), are stirred at reflux
14 hours, etc. systems be cooled to room temperature after add in 6N hydrochloric acid 20ml, again flow back 1 hour, separate organic phase, water phase dichloromethane
Alkane extracts 3 times, is dried after merging organic phase with anhydrous magnesium sulfate, removes organic solvent, and purifying obtains compound 4 as 3- (3-
Bromo- 6- picolines) -3- carbonyl propionic acid methyl esters, yield 78%, 6.3g；
D, compound 4 is dissolved in for 3- (the bromo- 6- picolines of 3-) -3- carbonyl propionic acid methyl esters 1g (3.5mmol) anhydrous
In ethyl alcohol 10ml, sodium ethoxide 0.8g (5.2mmol) is added in ice bath, 3- bromopropenes 0.9ml is added in while stirring
(5.0mmol), ambient temperature overnight reaction after reaction terminates, remove organic solvent, column chromatography (mobile phase：Volume ratio 1:10 second
Acetoacetic ester:Petroleum ether) purifying, compound 5 is obtained as 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters, production
Rate 91%, 1.0g；
E, compound 5 is dissolved in for 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters 1g (3.1mmol)
Volume ratio 3:1 dioxane:In the mixed solution of water, tetra-triphenylphosphine palladium catalyst 0.6g (0.45mmol), carbonic acid are added in
Sodium 1.3g (12mmol) and isopropenyl pinacol borate 0.85ml (3.9mmol), agitating and heating flow back 4 hours, treat system
Solvent, column chromatography (mobile phase are removed after being cooled to room temperature：Volume ratio 1:10 ethyl acetate:Petroleum ether) purifying, obtain chemical combination
Object 6 be 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- amylene-4 acid methyl esters, yield 87%, 0.76g；
F, under nitrogen protection, it is 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- penetenoic acids by compound 6
Methyl esters 1g (3.5mmol) is dissolved in dry methylene chloride solution 30ml, adds in Grubbs bis- generations catalyst 0.4g (0.4mmol),
Heating reflux reaction 14 hours, after reaction, the system for the treatment of is cooled to room temperature, and removes organic solvent, column chromatography (mobile phase：Body
Product ratio 1:5 ethyl acetate:Petroleum ether), it is 2,5- dimethyl -5- alkene -9- oxos-cycloheptane simultaneously [b] pyrrole to obtain compound 7
Pyridine -8- methyl formates, yield 44%, 0.42g；
G, it is 2,5- dimethyl -5- alkene -9- oxos-cycloheptane simultaneously [b] pyridine -8- formic acid first by compound 7 under ice bath
Ester 100mg (0.4mmol) is dissolved in absolute methanol 5ml, adds in sodium borohydride 20mg (0.53mmol), system warms naturally to room
Temperature after reaction 4 hours, adds water quenching to go out reaction, removing solvent, column chromatography (mobile phase：Volume ratio 1:3 ethyl acetate:Oil
Ether) purifying, compound 8 is obtained as 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane simultaneously [b] pyridine -8- methyl formates, yield
73%, 74mg；
H, it is 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane simultaneously [b] pyridine -8- methyl formates 100mg by compound 8
(0.4mmol) is dissolved in pyridine 10ml, and methylsufonyl chloride 50mg (0.45mmol), reaction 3.5 are added in after being heated to temperature 60 C
It after hour, is cooled to room temperature, water quenching is added to go out reaction, then extracted with dichloromethane 30ml and separate organic phase, the anhydrous sulphur of organic phase
Sour magnesium drying, column chromatography (mobile phase：Volume ratio 1:5 ethyl acetate:Petroleum ether) purifying, compound 9 is obtained as 2,5- diformazans
Base -5,8- diene-cycloheptane simultaneously [b] pyridine -8- methyl formates, yield 80%, 77mg；
I, it is 2,5- dimethyl -5,8- diene-cycloheptane simultaneously [b] pyridine -8- methyl formates 50mg by compound 9
(0.2mmol) is dissolved in absolute methanol 10ml, and a concentration of 0.5% palladium-carbon catalyst 18mg is added under ice bath, is passed through hydrogen, room temperature
Reaction is stirred overnight, removes solvent after reaction, (solvent is isolated and purified with thin layer chromatography method：Volume ratio 1:5
Ethyl acetate:Petroleum ether), it is (5- methyl -8- methyl formates)-cycloheptane simultaneously [b] pyridine -2- first to respectively obtain compound 10
Base, yield 84%, 42mg；
J, by compound 10 (5- methyl -8- methyl formates)-cycloheptane, simultaneously [b] pyridine -2- methyl 50mg (0.2mmol) is molten
In anhydrous tetrahydro furan, 4 times of lithium methide (0.8mmol) is added in, reaction adds 1ml water after terminating, 3ml is used after reaction is quenched
× 3 extractions, column chromatography (mobile phase after being dried with anhydrous magnesium sulfate：Volume ratio 1:1 ethyl acetate:Petroleum ether) purifying, it obtains
It is { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane simultaneously [b] pyridine -2- methyl to compound 11, yield 90%, 45mg.
K, by compound 11, for { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane, simultaneously [b] pyridine -2- methyl uses half
Preparative high performance liquid chromatography (SHIMADZU LC-20A), hand-type column CHIRALPAK ID (Lot No.ID00CE-QI011) are torn open
Point, enantiomter (mobile phase：Volume ratio 98:2 n-hexane:Ethyl alcohol), compound 212 is obtained as Cananga odorata alkali；Compound
13 be (5S, 8S)-Cananga odorata alkali.
Embodiment 3
A, compound 15- bromine 2- picolines 2.0g (12mmol) are dissolved in dichloromethane solution 30ml, system is placed in ice
Room temperature is warmed naturally to after the metachloroperbenzoic acid 2.9g (13.9mmol) that purity is 85% is added portionwise under bath, is stirred overnight
Reaction solution, is poured into the sodium sulfite solution of saturation is quenched after reaction by reaction, stirs 1 hour and uses dichloromethane later
Alkane 150ml is extracted 3 times, is merged organic phase, is dried with anhydrous magnesium sulfate, and nitrogen oxidation product Compound is obtained after removing organic solvent
2 be the bromo- 2- methyl-N- oxy picolinates of 5-, yield 93%, 2.0g；
B, under nitrogen protection, by compound 2, for the bromo- 2- methyl-N- oxy picolinates 1.0g (5.4mmol) of 5-, to be dissolved in acetonitrile molten
In liquid 20ml, trimethylsilyl cyanide 2.1g (21.6mmol) and triethylamine 2.2ml (16.2mmol) are sequentially added, is flowed back 12 hours
Afterwards, organic solvent is removed, it is COMBIFLASH that standby chromatography is suppressed in, mobile phase：Volume ratio 1:10 ethyl acetate:Petroleum ether
Purifying obtains compound 3 as the bromo- 6- methyl -2- cyanopyridines of 3-, yield 85%, 0.9g；
1H NMR (400MHz, Chloroform-d) δ 7.98 (d, J=8.2Hz, 1H), 7.24 (d, J=3.0Hz, 1H),
2.57(s,3H)；
C, under vacuum state, it is 40 that will contain mass ratio:60 crystallization water：Zinc chloride 8g (36.1mmol) is heated to melting and removes
Water under nitrogen protection, sequentially adds 1,2- dichloroethanes 75ml, compound 3 is the bromo- 6- methyl -2- cyanopyridines 5.5g of 3-
(27.9mmol), malonic acid monomethyl ester sylvite 13g (77mmol) and diisopropylethylamine 1.8ml (11.0mmol), are stirred at reflux
16 hours, etc. systems be cooled to room temperature after add in 6N hydrochloric acid 20ml, again flow back 1 hour, separate organic phase, water phase dichloromethane
Alkane extracts 3 times, is dried after merging organic phase with anhydrous magnesium sulfate, removes organic solvent, and purifying obtains compound 4 as 3- (3-
Bromo- 6- picolines) -3- carbonyl propionic acid methyl esters, yield 82%, 6.6g；
1H NMR (400MHz, Chloroform-d) δ 7.87 (d, J=8.2Hz, 1H), 7.14 (d, J=8.2Hz, 1H),
4.13(s,2H),3.71(s,3H),2.52(s,3H)；13C NMR(100MHz,Chloroform-d)δ193.16,168.26,
156.38,148.83,142.88,127.11,115.38,52.02,46.13,23.52.
D, compound 4 is dissolved in for 3- (the bromo- 6- picolines of 3-) -3- carbonyl propionic acid methyl esters 1g (3.5mmol) anhydrous
In ethyl alcohol 10ml, sodium ethoxide 1.0g (6.5mmol) is added in ice bath, 3- bromopropenes 1.0ml is added in while stirring
(5.6mmol), ambient temperature overnight reaction after reaction terminates, remove organic solvent, column chromatography (mobile phase：Volume ratio 1:10 second
Acetoacetic ester:Petroleum ether) purifying, compound 5 is obtained as 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters, production
Rate 97%, 1.1g；
1H NMR (400MHz, Chloroform-d) δ 7.86 (d, J=8.2Hz, 1H), 7.13 (d, J=8.2Hz, 1H),
5.92-5.78 (m, 1H), 5.11 (dd, J=17.1,1.6Hz, 1H), 5.03 (dd, J=10.1,1.5Hz, 1H), 4.64 (t, J
=7.2Hz, 1H), 3.66 (s, 3H), 2.76-2.69 (m, 2H), 2.52 (s, 3H)；13C NMR(100MHz,Chloroform-d)
δ195.39,170.86,156.84,149.94,143.37,135.10,127.48,119.46,117.62,54.80,52.62,
32.76,24.11.
E, compound 5 is dissolved in for 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters 1g (3.1mmol)
Volume ratio 3:1 dioxane:In the mixed solution of water, tetra-triphenylphosphine palladium catalyst 0.8g (0.6mmol), sodium carbonate are added in
1.5g (14.0mmol) and isopropenyl pinacol borate 1.0ml (4.6mmol), agitating and heating flow back 5 hours, treat that system is cold
But to removing solvent, column chromatography (mobile phase after room temperature：Volume ratio 1:10 ethyl acetate:Petroleum ether) purifying, obtain compound 6
For 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- amylene-4 acid methyl esters, yield 92%, 0.8g；
1H NMR (400MHz, Chloroform-d) δ 7.45 (d, J=7.9Hz, 1H), 7.23 (d, J=7.8Hz, 1H),
5.85 (ddt, J=17.0,10.2,6.8Hz, 1H), 5.12 (d, J=1.6Hz, 1H), 5.00 (dd, J=10.0,1.7Hz,
1H), 4.81 (d, J=0.9Hz, 1H), 4.74 (t, J=7.2Hz, 1H), 3.65 (s, 3H), 2.76-2.68 (m, 2H), 2.54
(s, 3H), 2.03 (d, J=1.2Hz, 3H)；13C NMR(100MHz,Chloroform-d)δ196.66,170.96,156.04,
148.76,138.58,135.00,132.71,125.94,118.54,116.82,114.23,54.04,51.93,36.94,
32.44,23.53.；
F, under nitrogen protection, it is 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- penetenoic acids by compound 6
Methyl esters 1g (3.5mmol) is dissolved in dry methylene chloride solution 30ml, adds in Grubbs bis- generations catalyst 0.5g (0.5mmol),
Heating reflux reaction 16 hours, after reaction, the system for the treatment of is cooled to room temperature, and removes organic solvent, column chromatography (mobile phase：Body
Product ratio 1:5 ethyl acetate:Petroleum ether), it is 2,5- dimethyl -5- alkene -9- oxos-cycloheptane simultaneously [b] pyrrole to obtain compound 7
Pyridine -8- methyl formates, yield 53%, 0.5g；
1H NMR (400MHz, Chloroform-d) δ 12.35 (s, 1H), 7.76 (d, J=8.2Hz, 1H), 7.26 (d, J
=8.2Hz, 1H), 6.08 (t, J=7.4Hz, 1H), 3.85 (s, 3H), 2.69 (s, 3H), 2.52 (d, J=7.0Hz, 2H),
2.09(s,3H)；13C NMR(100MHz,Chloroform-d)δ171.92,165.08,157.15,149.75,135.61,
134.96,134.75,132.44,130.65,124.26,106.05,52.54,31.38,24.93,21.88.
G, it is 2,5- dimethyl -5- alkene -9- oxos-cycloheptane simultaneously [b] pyridine -8- formic acid first by compound 7 under ice bath
Ester 100mg (0.4mmol) is dissolved in absolute methanol 5ml, adds in sodium borohydride 30mg (0.8mmol), system warms naturally to room
Temperature after reaction 5 hours, adds water quenching to go out reaction, removing solvent, column chromatography (mobile phase：Volume ratio 1:3 ethyl acetate:Oil
Ether) purifying, compound 8 is obtained as 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane simultaneously [b] pyridine -8- methyl formates, yield
78%, 80mg；
1H NMR (400MHz, DMSO-d6) δ 7.71 (d, J=7.9Hz, 1H), 7.28 (d, J=7.9Hz, 1H), 6.03-
5.96 (m, 1H), 5.40 (d, J=5.4Hz, 1H), 4.81 (t, J=5.9Hz, 1H), 3.66 (s, 3H), 3.49 (dt, J=
10.8,6.6Hz,1H),2.52(s,3H),2.27–2.07(m,2H),2.04(s,3H)；
H, it is 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane simultaneously [b] pyridine -8- methyl formates 100mg by compound 8
(0.4mmol) is dissolved in pyridine 10ml, is added in methylsufonyl chloride 60mg (0.5mmol) after being heated to temperature 60 C, is reacted 5 hours
Afterwards, it is cooled to room temperature, water quenching is added to go out reaction, then organic phase, organic phase anhydrous magnesium sulfate are separated with dichloromethane 30ml extractions
It is dry, column chromatography (mobile phase：Volume ratio 1:5 ethyl acetate:Petroleum ether) purifying, compound 9 is obtained as 2,5- dimethyl -5,
8- diene-cycloheptane simultaneously [b] pyridine -8- methyl formates, yield 87%, 84mg；
1H NMR (400MHz, Chloroform-d) δ 1H NMR (400MHz, CDCl3) δ 7.80 (d, J=8.2Hz, 1H),
7.74 (s, 1H), 7.15 (d, J=8.2Hz, 1H), 5.85 (t, J=7.3Hz, 1H), 3.82 (s, 3H), 2.67 (d, J=
7.2Hz,2H),2.62(s,3H),2.11(s,3H)；13C NMR(100MHz,Chloroform-d)δ167.15,156.77,
152.60,138.30,135.85,135.17,134.96,133.33,126.87,122.27,52.60,24.95,24.77,
22.29.
I, it is 2,5- dimethyl -5,8- diene-cycloheptane simultaneously [b] pyridine -8- methyl formates 50mg by compound 9
(0.2mmol) is dissolved in absolute methanol 10ml, and a concentration of 0.5% palladium-carbon catalyst 20mg is added under ice bath, is passed through hydrogen, room temperature
Reaction is stirred overnight, removes solvent after reaction, (solvent is isolated and purified with thin layer chromatography method：Volume ratio 1:5
Ethyl acetate:Petroleum ether), it is (5- methyl -8- methyl formates)-cycloheptane simultaneously [b] pyridine -2- first to respectively obtain compound 10
Base, yield 96%, 45mg.
1H NMR (400MHz, Chloroform-d) δ 6.93 (d, J=7.7Hz, 1H), 7.31 (d, J=7.7Hz, 1H),
3.04–2.95(m,1H),1.86–1.74(m,2H),2.01–1.93(m,1H),2.17–2.07(m,1H),2.70–2.61(m,
1H), 3.31 (d, J=14.6,2.7Hz, 1H), 3.36 (dd, J=14.6,9.7Hz, 1H), 1.32 (d, J=7.3Hz, 3H),
3.64(s,3H),2.49(s,3H)；13C NMR(100MHz,Chloroform-d)δ157.19,121.16,136.05,37.41,
32.05,28.96,41.80,40.26,154.46,137.68,175.49,51.43,18.66,23.60.
J, by compound 10 (5- methyl -8- methyl formates)-cycloheptane, simultaneously [b] pyridine -2- methyl 50mg (0.2mmol) is molten
In anhydrous tetrahydro furan, 5 times of lithium methide (1.0mmol) is added in, reaction adds 1ml water after terminating, 3ml is used after reaction is quenched
× 3 extractions, column chromatography (mobile phase after being dried with anhydrous magnesium sulfate：Volume ratio 1:1 ethyl acetate:Petroleum ether) purifying, it obtains
It is { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane simultaneously [b] pyridine -2- methyl to compound 11, yield 95%,
44.2mg.
1H NMR (600MHz, Chloroform-d) δ 7.31 (d, J=7.7Hz, 1H), 6.93 (d, J=7.7Hz, 1H),
3.27–3.23(m,1H),3.05–3.00(m,2H),2.49(s,3H),1.89–1.84(m,1H),1.82–1.75(m,1H),
1.73-1.67 (m, 1H), 1.64-1.59 (m, 1H), 1.49-1.41 (m, 1H), 1.31 (d, J=7.2Hz, 3H), 1.27 (s,
3H),1.24(s,3H).13C NMR(150MHz,Chloroform-d)δ159.59,154.86,137.37,135.92,
121.38,74.07,47.59,39.52,34.06,30.06,27.81,27.14,26.46,24.10,18.96.
K, by compound 11, for { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane, simultaneously [b] pyridine -2- methyl uses half
Preparative high performance liquid chromatography (SHIMADZU LC-20A), hand-type column CHIRALPAK ID (Lot No.ID00CE-QI011) are torn open
Point, enantiomter (mobile phase：Volume ratio 98:2 n-hexane:Ethyl alcohol), compound 12 is obtained as Cananga odorata alkali；Compound 13
For (5S, 8S)-Cananga odorata alkali.
Compound 12 is Cananga odorata alkali：1H NMR (400MHz, Chloroform-d) δ 7.33 (d, J=7.7Hz, 1H),
6.94 (d, J=7.7Hz, 1H), 3.30-3.22 (m, 1H), 3.09-3.01 (m, 2H), 2.50 (s, 3H), 1.91-1.82 (m,
1H),1.81–1.74(m,1H),1.74–1.66(m,1H),1.66–1.58(m,1H),1.50–1.38(m,1H),1.31(d,J
=7.2Hz, 3H), 1.27 (s, 3H), 1.24 (s, 3H) .13C NMR (101MHz, Chloroform-d) δ 159.10,154.36,
135.76,121.11,109.99,73.70,47.11,38.91,36.26,33.66,27.40,26.89,26.00,23.60,
18.60.
Compound 13 is (5S, 8S)-Cananga odorata alkali：1H NMR (400MHz, Chloroform-d) δ 7.33 (d, J=
7.7Hz, 1H), 6.94 (d, J=7.7Hz, 1H), 3.30-3.22 (m, 1H), 3.09-3.01 (m, 2H), 2.50 (s, 3H),
1.91–1.82(m,1H),1.81–1.74(m,1H),1.74–1.66(m,1H),1.66–1.58(m,1H),1.50–1.38(m,
1H), 1.31 (d, J=7.2Hz, 3H), 1.27 (s, 3H), 1.24 (s, 3H) .13C NMR (101MHz, Chloroform-d) δ
159.10,154.36,135.76,121.11,109.99,73.70,47.11,38.91,36.26,33.66,27.40,26.89,
26.00,23.60,18.60。
Embodiment 4
By any one compound 12 that embodiment 1-3 is obtained be Cananga odorata alkali and its enantiomter compound 13 is
(5S, 8S)-Cananga odorata alkali hybridizes high-resolution mass spectrometer with American AB SCIEX companies Qstar Elite quadrupole rods-flight time
Its accurate molecular weight is measured, optical value is measured with Rudolph RS Autopol VI automatic polarimeter, uses
Chirascan circular dichroisms spectrometer measuring EDC and with 3.4 software meters of Germany COSMOlogic GmbH＆Co.KG TmoleX
The high resolution mass spectrum of its relatively more determining absolute configuration of calculation ECD spectrums, Cananga odorata alkali (Cananodine) and its enantiomter is shown in figure
1- Fig. 2.
Claims (1)
- A kind of 1. fully synthetic and enantiomter the method for splitting of natural products (±)-Cananga odorata alkali, it is characterised in that the party Natural products (±)-Cananga odorata alkali in method is to pass through tetrahydrofuran/methyl as substrate using natural products (±)-atisine G Lithium reacts, and obtains (±)-Cananga odorata alkali and its enantiomter, then with chirality semipreparative high performance liquid chromatography instrument, carries out pair The fractionation of isomers is answered, structural formula is：Wherein：Compound 1 is 5- bromine 2- picolines；Compound 2 is N- oxygen -5- bromine 2- picolines；Compound 3 is 6- cyano -5- bromine 2- picolines；Compound 4 is 3- (the bromo- 6- picolines of 3-) -3- carbonyl propionic acid methyl esters；Compound 5 is 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters；Compound 6 is 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- amylene-4 acid methyl esters；Compound 7 is 2,5- dimethyl -5- alkene -9- oxos-cycloheptane simultaneously [b] pyridine -8- methyl formates；Compound 8 is 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane simultaneously [b] pyridine -8- methyl formates；Compound 9 is 2,5- dimethyl -5,8- diene-cycloheptane simultaneously [b] pyridine -8- methyl formates；Compound 10 is (5- methyl -8- methyl formates)-cycloheptane simultaneously [b] pyridine -2- methyl/{ (±)-atisine G }；Compound 11 is { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane simultaneously [b] pyridine -2- methyl/{ (±)-Cananga odorata Alkali }；Compound 12 is Cananga odorata alkali；Compound 13 is (5S, 8S)-Cananga odorata alkali；Concrete operations follow these steps to carry out：A, compound 1 is dissolved in for 5- bromine 2- picolines 2.0g in dichloromethane solution, system is placed under ice bath and is added portionwise After 85% metachloroperbenzoic acid 2.9g of purity, room temperature is warmed naturally to, reaction is stirred overnight, after reaction falls reaction solution Enter into the sodium sulfite solution of saturation and be quenched, stirring is extracted 3 times after 1 hour with dichloromethane, merges organic phase, with anhydrous sulphur Sour magnesium drying obtains nitrogen oxidation product Compound 2 as the bromo- 2- methyl-N- oxy picolinates of 5- after removing organic solvent；B, under nitrogen protection, compound 2 is dissolved in for the bromo- 2- methyl-N- oxy picolinates 1.0g of 5- in acetonitrile solution, added successively Enter trimethylsilyl cyanide 2.1g and triethylamine 2.2ml, after flowing back 12 hours, remove organic solvent, purifying, obtaining compound 3 is The bromo- 6- methyl -2- cyanopyridines of 3-；C, under vacuum state, mass ratio 40 will be contained:60 crystallization water:Zinc chloride 7.2g-8.0g is heated to melting water removal, in nitrogen Under protection, 1,2- dichloroethanes is sequentially added, compound 3 is the bromo- 6- methyl -2- cyanopyridines 5.5g of 3-, malonic acid monomethyl ester Sylvite 11g-13g and diisopropylethylamine 1.5g-1.8g is stirred at reflux 12-16 hours, 6N is added in after system is cooled to room temperature Hydrochloric acid flows back 1 hour again, separates organic phase, and water phase is extracted 3 times with dichloromethane, and anhydrous magnesium sulfate is used after merging organic phase It is dry, organic solvent is removed, purifying obtains compound 4 as 3- (the bromo- 6- picolines of 3-) -3- carbonyl propionic acid methyl esters；D, compound 4 is dissolved in for 3- (the bromo- 6- picolines of 3-) -3- carbonyl propionic acid methyl esters 1.0g in absolute ethyl alcohol, ice bath Middle addition sodium ethoxide 0.6g-1.0g, 3- bromopropene 0.7ml-1.0ml are added in while stirring, and ambient temperature overnight reaction removes organic Solvent, column chromatography purifying obtain compound 5 as 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters；E, compound 5 is dissolved in dioxane for 2- (the bromo- 6- picolines -2- formoxyls of 3-) -4- allyl acetic acid methyl esters 1.0g In the mixed solution of water, tetra-triphenylphosphine palladium catalyst 0.4g-0.8g, sodium carbonate 1g-1.5g, isopropenyl boric acid frequency are added in Which alcohol ester 0.71ml-1.0ml, agitating and heating flow back 3-5 hours, and solvent is removed after system is cooled to room temperature, and column chromatography purifies, Compound 6 is obtained as 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- amylene-4 acid methyl esters；F, under nitrogen protection, it is 2- (3- isopropenyl -6- picoline -2- formoxyls) -4- amylene-4 acid methyl esters by compound 6 1.0g is dissolved in dichloromethane solution, addition Grubbs bis- generations catalyst 0.3g-0.5g, heating reflux reaction 12-16 hours, The system for the treatment of is cooled to room temperature, and removes organic solvent, and column chromatography obtains compound 7 as 2,5- dimethyl -5- alkene -9- oxos-cycloheptyl Alkane simultaneously [b] pyridine -8- methyl formates；G, it is 2,5- dimethyl -5- alkene -9- oxos-cycloheptane simultaneously [b] pyridine -8- methyl formates by compound 7 under ice bath 100mg is dissolved in absolute methanol, adds in sodium borohydride 15mg-30mg, warms naturally to room temperature, after reacting 3-5 hours, adds water It is quenched reaction, removes solvent, column chromatography, purifying obtains compound 8 as 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane simultaneously [b] Pyridine -8- methyl formates；H, by compound 8, for 2,5- dimethyl -5- alkene -9- hydroxyls-cycloheptane, simultaneously [b] pyridine -8- methyl formates 100mg is dissolved in pyrrole In pyridine, temperature 60 C is heated to, adds methylsufonyl chloride 45mg-60mg, after reacting 3-5 hours, is cooled to room temperature, adds water quenching It goes out reaction, then organic phase is separated with dichloromethane extraction, organic phase is dried with anhydrous magnesium sulfate, and column chromatography purifying obtains chemical combination Object 9 is 2,5- dimethyl -5,8- diene-cycloheptane simultaneously [b] pyridine -8- methyl formates；I, by compound 9, for 2,5- dimethyl -5,8- diene-cycloheptane, simultaneously [b] pyridine -8- methyl formates 50mg is dissolved in no water beetle In alcohol, palladium-carbon catalyst 15mg-20mg is added under ice bath, is passed through hydrogen, be stirred overnight at room temperature reaction, removes solvent, uses thin layer Chromatographic methods isolate and purify, and it is (5- methyl -8- methyl formates)-cycloheptane simultaneously [b] pyridine -2- first to obtain compound 10 Base；J, by compound 10, for (5- methyl -8- methyl formates)-cycloheptane, simultaneously [b] pyridine -2- methyl 50mg is dissolved in dry four In hydrogen furans, by system as at -10 DEG C of temperature, 3-5 times of lithium methide is added in, after 1 hour of reaction, water quenching is added to go out reaction, It is extracted 3 times with dichloromethane again, merges organic phase, after being dried with anhydrous magnesium sulfate, cross filter solid, filtrate removes solvent It is { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane simultaneously [b] pyridine -2- methyl to close object 11；K, by compound 11, for { (5- methyl -8- (2- methyl 1- propyl alcohol)) }-cycloheptane, simultaneously [b] pyridine -2- methyl is prepared with half Type high performance liquid chromatography is split, and it be Cananga odorata alkali and compound 13 for (5S, 8S)-Cananga odorata alkali to obtain compound 12.
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| CN112409260A (en) * | 2020-10-26 | 2021-02-26 | 江苏康缘药业股份有限公司 | Alkaloid compound and preparation method and application thereof |
| CN113402461A (en) * | 2021-06-21 | 2021-09-17 | 中国科学院新疆理化技术研究所 | Method for preparing guaiazupyridine type sesquiterpene alkaloid |
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| DONALD CRAIG等: "Total Synthesis of the Cytotoxic Guaipyridine Sesquiterpene Alkaloid (+)-Cananodine", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
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| CN112409260A (en) * | 2020-10-26 | 2021-02-26 | 江苏康缘药业股份有限公司 | Alkaloid compound and preparation method and application thereof |
| CN113402461A (en) * | 2021-06-21 | 2021-09-17 | 中国科学院新疆理化技术研究所 | Method for preparing guaiazupyridine type sesquiterpene alkaloid |
| CN113402461B (en) * | 2021-06-21 | 2023-02-03 | 中国科学院新疆理化技术研究所 | Method for preparing guaiazupyridine type sesquiterpene alkaloid |
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