CN105399672A

CN105399672A - Reversible acetylcholinesterase inhibitor huperzine-A synthesis method

Info

Publication number: CN105399672A
Application number: CN201410471645.3A
Authority: CN
Inventors: 周伟锋; 刘桂连; 施翔; 戴荣华; 鞠涛; 李玉灵; 王鹏鹏
Original assignee: Shanghai Hongjing Biotechnology Co Ltd
Current assignee: SHANGHAI HONGJING BIOTECHNOLOGY CO., LTD.
Priority date: 2014-09-16
Filing date: 2014-09-16
Publication date: 2016-03-16
Anticipated expiration: 2034-09-16
Also published as: CN105399672B

Abstract

The present invention discloses a reversible acetylcholinesterase inhibitor huperzine-A synthesis method, wherein the route is defined in the specification. The method of the present invention has advantages of easily-available raw materials, simple operation, high yield, low cost, high purity of the final product, easy quality control and the like, and is suitable for industrial production.

Description

The synthetic method of reversibility acetylcholinesterase depressant selagine

Technical field

The present invention relates to a kind of preparation method of compound, particularly relate to a kind of synthetic method of reversibility acetylcholinesterase depressant selagine ((-)-HuperzineA).

Background technology

Senile dementia is also known as alzheimer's disease (Alzheimerdisease, AD), and be that a kind of central nervous system degeneration is sick, insidious onset, the course of disease is chronic progressive external.Main manifestations is the neuropsychic symptoms such as gradual memory obstacle, cognition dysfunction, personality change and aphasis, has a strong impact on social activity, work and vital function.The cause of disease and the pathogenesis of AD are not yet illustrated, but according to relevant research, Cholinergic defect and senile dementia closely related.

At present along with Chinese society aging trend, China's more than 60 years old elderly population have reached about 1.44 hundred million at present according to statistics, and in the near future, China will enter aging society.The problem that simultaneous one is very important---the sickness rate of senile dementia is increasing year by year.Investigation finds: northern China suffer from mean age of senile dementia be 75,76 years old, the age of suffering from vascular dementia is many at about 68 years old.The ratio of suffering from severe senile dementia in over-65s crowd reaches more than 5%, and by 80 years old, this ratio just rose to 15-20%.Senile dementia threatens one of China citizen the most serious healthy disease this century by becoming.Therefore, find the active drug for the treatment of senile dementia, become the study hotspot of field of medicaments.

Using medicine to strengthen Cholinergic is the most frequently used method of prevention and therapy senile dementia, and this kind of drug main will comprise the precursor providing vagusstoff, excited cholinergic receptor and suppress choline enzyme to reduce the preparation etc. of the metabolism of vagusstoff.Wherein, acetylcholinesterase (AchE) inhibitor is that medication is the widest clinically at present, simultaneously also by the class medicine extensively received.

Selagine ((-)-HuperzineA), chemistry (5R by name, 9R, 11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring cycloocta--2 (1H)-pyridone, it is the potent low toxicity acetylcholinesterase depressant of a kind of reversibility, is initiated by Shanghai institute of materia medica of China.It is a kind of new alkaloids of separation and Extraction from plants of Huperzia Herba Lycopodii serrati, has obvious anticholinesterase effect.Clinical study shows, selagine can improve senile Memory Impairment, has certain curative effect, significantly can improve the memory of senile dementia patients, cognition and behavioral function to old and presenium dysmnesia.Selagine is a kind of medicine of generally acknowledging the most rising treatment senile dementia at present, such medicine is most in the past to be extracted from plant, but plant Herba Lycopodii serrati system used herbaceous plant, be longer than dark and damp place, hills, growth cycle reaches 8-10, along with the exploitation in market, natural resource progressively show scarcity, simple separation and Extraction, are difficult to meet the market requirement gradually expanded, therefore, the method that applied chemistry is synthesized obtains qualified selagine and has the good market development and application prospect.

At present, the preparation about selagine of bibliographical information, mainly contains following several method:

1) route 1 is (with reference to Qizn, L.G; Ji, RY.Chin.J.Med.Chem.1992.2 (2) .1-8)

2) route 2 is (with reference to Chassaing, C.; Haudrechy, A.; Langlois, Y.Synth.Commun., 1997,27,61)

3) route 3 is (with reference to Yamada, F.Kozikowski.A.P; Reddy, ER; Pang .Y.P; Miller.J.H.; McKinney.J.Am.Chem.Soc.1991.113.4695)

4) route 4 (with reference to J.Org.Chem.1993,58,7660)

5) route 5 is (with reference to Org.ProcessRes.Dev.2012,16,635-642; WO2009/120774A2)

Route 1 is for starting raw material and methyl iodide carry out alkylation reaction with 6-hydroxy-2-methyl Nikithan, obtain compound 13 through Lithium aluminum hydride reduction simultaneously, compound 14 is generated with sulfur oxychloride through halogenating reaction under phenyl lithium and formaldehyde effect, compound 15 is obtained again respectively by sodium cyanide and methanolic hydrogen chloride solution, under sodium hydride catalysis, cyclization obtains important intermediate 16, then through Methylacrylaldehyde addition, eliminate under high-temperature alkaline, witting reacts, potassium hydroxide is hydrolyzed, this rearrangement of storehouse orange red, hydrolysis reaction obtains target product, this route starting raw material is not easy to obtain, and use violent in toxicity sodium cyanide in reaction, raceme compound 21 is directly used in the next step without necessity effectively splits simultaneously, qualified simple optics structural object product cannot be obtained by causing, therefore this route is not suitable for suitability for industrialized production.

Route 2 is for starting raw material obtains compound 18 under NBS effect with 2-methoxyl group-6-picoline, compound 19 is obtained through twice allyl bromide 98 process, under NaOH effect, carry out oxidizing reaction with ozone again and obtain compound 15, important intermediate 16 is obtained through cyclization under sodium hydride effect, then with Methylacrylaldehyde addition, eliminate under high-temperature alkaline, witting reacts, potassium hydroxide is hydrolyzed, this rearrangement of storehouse orange red, hydrolysis reaction obtains target product, although this route avoids the violent in toxicity sodium cyanide in route 1, step is also relatively short, but this route needs to use ozone to react as oxygenant, thus require higher to production unit, the simultaneously larger also not easy to operate and monitoring of danger, and this route in the reaction raceme the same as route 1 compound 21 is directly used in the next step without necessity effectively splits, qualified simple optics structural object product cannot be obtained by causing, therefore this route is not suitable for suitability for industrialized production.

Route 3 be with compound 16 for starting raw material in acid condition and (-)-8 phenylmenthol be obtained by reacting compound 25, be separated obtaining compound 20 respectively by Michael-A Dao condensation, dehydration, preparative chromatography, compound 21 is obtained again through witting reaction, isomerization, compound 11 is generated under lithium aluminium hydride and Jones reagent effect, obtain important intermediate 22 through this rearrangement of storehouse orange red in ethanol again, finally hydrolysis obtains target product.Although this route avoids ozone in violent in toxicity sodium cyanide in route 1 and route 2, but need to use preparative chromatography and be separated preparing in intermediate 24 process, require higher to full-scale plant, and production cost is expensive, this route has used very easily quick-fried trinitride when the preparation of compound 26 simultaneously, bring serious potential safety hazard to large-scale production, therefore this route is not suitable for suitability for industrialized production.

Route 4 is for starting raw material is under triphenylphosphine, tetramethyl guanidine, plumbic acetate effect and 2-methylene radical-1 with compound 16, ammediol diacetate reacting generating compound 26, DL body compound 27 is obtained by reacting through Witting, split by benzenethiol under Diisopropyl azodicarboxylate catalysis and obtain E formula compound 28, obtain important intermediate 29 through 20% aqueous sodium hydroxide solution hydrolysis, obtain target product respectively by this rearrangement of storehouse orange red, amide hydrolysis, double-bond rearrangement.This route only mentions the fractionation of cis-trans-isomer and the fractionation of not mentioned chiral center, and therefore this route cannot obtain qualified simple optics structural object product by causing.Simultaneously the same with route 3, dangerously explosive trinitride has been used when the preparation of compound 31, higher to operational requirement, bring great potential safety hazard to production simultaneously.Be not suitable for large-scale industrial production.

Route 5 is with 1, 4-cyclohexanedione single ketal is obtained by reacting intermediate 2-hydroxyl-6-ethylene ketal base-5 with Methyl propiolate and ammonia at methanol solution mesohigh pyrocondensation, 6, 7, 8-tetrahydroquinoline, again through alkylation, deprotection, esterification, chirality Guan Huan etc. are obtained by reacting optical homochiral selagine, used by this route, Methyl propiolate price is more expensive, domestic production producer is few, and this step reaction needed is used ammonia and is brought certain inconvenience to feeding intake, need to use high-temperature high-voltage reaction simultaneously, higher and there is certain danger to equipment requirements, chiral catalyst SL-T002-01 only has an external Reagent Company to sell in addition, expensive, be difficult to provide on a large scale.Therefore, scale operation cannot be carried out.

Summary of the invention

The technical problem to be solved in the present invention is to provide a kind of synthetic method of reversibility acetylcholinesterase depressant selagine ((-)-HuperzineA), i.e. a kind of synthetic method of selagine of simple optical texture newly, method of the present invention simplifies operational condition and process, and has advantages such as improving yield, reduce costs.

For solving the problems of the technologies described above, the synthetic method of reversibility acetylcholinesterase depressant selagine of the present invention, its route is as follows:

For the synthetic method of above-mentioned reversibility acetylcholinesterase depressant selagine, comprise step:

(1) preparation of compound 2

With Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal for raw material, in Pyrrolidine/Glacial acetic acid catalyst system, generate enamine, then obtain with vinyl cyanide alkylated reaction.

Specifically can be as follows:

After the reaction of Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal, Pyrrolidine and Glacial acetic acid, add vinyl cyanide and react again, obtain compound 2 (2-cyanoethyl-Isosorbide-5-Nitrae-cyclohexanedione-4-monoethylene glycol ketal);

Wherein, the amount ratio of described Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal, Pyrrolidine, Glacial acetic acid and vinyl cyanide is 200 ~ 1000g:90 ~ 460g:500 ~ 5000mL:80 ~ 400g;

Preferably, Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal, Pyrrolidine and Glacial acetic acid back flow reaction 3 ~ 20h, drip vinyl cyanide back flow reaction 10 ~ 30h again;

In addition, in step (1), can after TLC (thin-layer chromatography) detection reaction, reclaim under reduced pressure Glacial acetic acid, gained oily matter water-insoluble organic solvent dissolves, washing, and salt is washed (as saturated common salt water washing), dry bath, suction filtration, concentrates to obtain product.Wherein, water-insoluble organic solvent comprises: one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether etc.

(2) preparation of compound 3

With compound 2 for raw material, under protection of inert gas, carry out cyclization reaction via silica gel load sulfuric acid catalyst, obtain compound 3.

Specifically can be as follows:

Under rare gas element (comprising: nitrogen), compound 2 and silica gel load sulfuric acid catalyst react, and obtain compound 3 (2-hydroxyl-6-ethylene ketal base-5,6,7,8-tetrahydroquinoline);

Wherein, silica gel load sulfuric acid catalyst by routine preparation method (as reference: Li Jianwei etc. the research of silica gel load sulfuric acid catalysis esterification. application chemical industry .2005,34 volumes the 6th phase, 364-365) obtained;

Compound 2 is preferably 100 ~ 500:5 ~ 40 with the weight ratio of silica gel load sulfuric acid catalyst;

The condition optimization of reaction is 100 ~ 200 DEG C of reaction 10 ~ 40h;

In addition, in step (2), after TLC (thin-layer chromatography) detection reaction, glycol dimethyl ether can be added and is heated to backflow, product is entirely molten, suction filtration silica gel load sulfuric acid catalyst, and filtrate concentrates (with desolventizing), freezing crystallization, suction filtration, dry, obtain product.

(3) preparation of compound 4

In the mixed system of water and water-insoluble organic solvent, using mineral alkali as acid binding agent, and under phase-transfer catalyst and water soluble silver salt, compound 3 and methylating reagent react, and obtain compound 4;

Specifically can be as follows:

In the mixed system of water and water-insoluble organic solvent, mineral alkali, phase-transfer catalyst and water soluble silver salt, compound 3 and methylating reagent react, and obtain compound 4 (2-methoxyl group-6-ethylene ketal base-5,6,7,8-tetrahydroquinoline);

Wherein, water-insoluble organic solvent comprises: one or more in methylene dichloride, methyl tertiary butyl ether, toluene etc., preferable methyl tertbutyl ether;

The mixed volume ratio of water and water-insoluble organic solvent is preferably 1:2 ~ 1:5, more preferably 1:2.

Mineral alkali comprises: one or more in sodium hydroxide or potassium hydroxide, lithium hydroxide, hydrated barta etc.; Preferred sodium hydroxide;

Phase-transfer catalyst comprises: one or more in TBAB (tetrabutyl phosphonium bromide by), benzyltriethylammoinium chloride, benzyl trimethyl ammonium chloride, benzyl tributyl ammonium chloride, 4-propyl ammonium chloride etc.;

Water soluble silver salt comprises: the one in silver carbonate, Silver monoacetate etc. or its mixture; Preferred silver carbonate;

Methylating reagent comprises: the one in methyl iodide, monobromethane etc. or its mixture; Preferred methyl iodide.

The mol ratio of mineral alkali, phase-transfer catalyst, compound 3, water soluble silver salt and methylating reagent is preferably 1 ~ 1.5:0.2 ~ 0.5:1:0.5 ~ 1.

Amount ratio as compound 3, phase-transfer catalyst, methyl tertiary butyl ether, aqueous sodium hydroxide solution (0.5 ~ 2mol/L), silver carbonate and methyl iodide is preferably 50 ~ 300g:0.5 ~ 10g:500 ~ 3000mL:200 ~ 1500mL:70 ~ 400g:100 ~ 600g;

The condition optimization of reaction is 20 ~ 35 DEG C of reaction 5 ~ 20h;

In addition, in step (3), after TLC (thin-layer chromatography) detection reaction, can filter, (as saturated common salt water washing) twice that salt is washed, concentrated, obtain product.

(4) preparation of compound 5

Under phase-transfer catalyst, with compound 4 for raw material, in acidic aqueous solution, obtain through backflow deprotection reaction.

Specifically can be as follows:

Under phase-transfer catalyst, compound 4 and acidic aqueous solution react, and obtain compound 5 (2-methoxyl group-6-oxo-5,6,7,8-tetrahydroquinoline)

Wherein, phase-transfer catalyst comprises: one or more in TBAB (tetrabutyl phosphonium bromide by), benzyltriethylammoinium chloride, benzyl trimethyl ammonium chloride, benzyl tributyl ammonium chloride, 4-propyl ammonium chloride etc.;

Acidic aqueous solution comprises: the tosic acid aqueous solution (preferred mass concentration is 5 ~ 50%, more preferably 10%).

The amount ratio of compound 4, acidic aqueous solution and phase-transfer catalyst is preferably 50 ~ 600g:200 ~ 3000mL:0.5 ~ 10g;

The condition optimization of reaction is back flow reaction 8 ~ 20h;

In addition, in step (4), after TLC (thin-layer chromatography) detection reaction, room temperature can be cooled to, pH9-12 is adjusted to alkali, use organic solvent (comprising: in ethyl acetate, methylene dichloride, methyl tertiary butyl ether etc. one or more) extraction again, merge organic layer, salt washing (as saturated common salt water washing), anhydrous sodium sulfate drying, suction filtration, concentrated, obtain product.

(5) preparation of compound 6

With compound 5 for raw material, with diisopropyl carbonate as solvent, with highly basic as pulling out hydrogen agent, carrying out carbonyl alpha-position alkylated reaction and obtaining;

Specifically can be as follows:

(comprising: under nitrogen, argon gas (being the aqueous vapor in isolated air, in case sodium hydrogen catches fire), compound 5 reacts with diisopropyl carbonate and highly basic at rare gas element, obtain compound 6 (2-methoxyl group-5-butyloxycarbonyl-6-oxo-5,6,7,8-tetrahydroquinoline);

Wherein, highly basic comprises: the one in sodium hydride or potassium hydride KH etc. or its mixture; Preferred sodium hydride;

The amount ratio of compound 5, diisopropyl carbonate and highly basic is preferably 50 ~ 300g:500 ~ 3000mL:15 ~ 90g;

The condition optimization of reaction is 50 ~ 120 DEG C of reaction 0.5 ~ 8h;

In addition, in step (5), can after TLC (thin-layer chromatography) detection reaction, concentrating under reduced pressure (recycling design), concentrated solution is poured in frozen water, pH1-2 is adjusted to hydrochloric acid, (comprising: ethyl acetate with organic solvent, methylene dichloride, one or more in methyl tertiary butyl ether etc.) aqueous layer extracted, discard organic layer, water layer saturated solution of sodium carbonate is adjusted to pH7-10, organic solvent is used (to comprise: ethyl acetate again, methylene dichloride, one or more in methyl tertiary butyl ether etc.) extraction, merge organic layer, salt is washed (as saturated common salt water washing), dry, suction filtration, concentrated, obtain product.

(6) preparation of compound 7

Under protection of inert gas, with Tanaiphos Phosphine ligands as chiral catalyst, palladium catalyst is as Phosphine ligands complexing body, and using organic bases as acid binding agent, and in aprotic solvent, compound 6 and the ester condensation of 1,3-methylene radical propylene glycol two Tricholroacetic Acid obtain.

Specifically can be as follows:

Under rare gas element (comprising: nitrogen), aprotic solvent, Tanaiphos phosphorus part, palladium catalyst and organic bases exist, 1,3-bis-methylene propylene glycol two trichloroacetic esters and compound 6 react, obtain compound 7 ((5R, 9R) the pungent and pyridine of-2-methoxyl group-5-butyloxycarbonyl-7-methylene radical-11-oxo-5,9-methylene ring);

Wherein, aprotic solvent comprises: one or more in acetone, dme (DME), methylene dichloride, chloroform, tetrahydrofuran (THF) etc.; Preferred DME;

Tanaiphos phosphorus part can method routinely be prepared, as being prepared with reference to the method for Tetrahedron:Asymmetry15 (2004) 91 – 102;

Palladium catalyst (organic palladium of 0 valency) comprising: diallyl Palladous chloride, four triphenyl phosphorus palladiums, (dppf) ₂pdCl ₂deng in one or more; Preferred diallyl Palladous chloride;

Organic bases comprises: be one or more in DBU (1,8-diazacyclo [5,4,0] hendecene-7), TMG (tetramethyl guanidine), pyridine, triethylamine and DMAP (4-N, N-Dimethylamino pyridine) etc.

The mol ratio of Tanaiphos phosphorus part, palladium catalyst, organic bases, 1,3-bis-methylene propylene glycol two trichloroacetic esters and compound 6 is preferably 0.02 ~ 0.04:0.01 ~ 0.02:2 ~ 3:1 ~ 1.5:1;

Amount ratio as preferred anhydrous DME, Tanaiphos phosphorus part, diallyl Palladous chloride, organic bases, 1,3-bis-methylene propylene glycol two trichloroacetic esters and compound 6 is preferably 20 ~ 1000ml:5 ~ 50g:0.2 ~ 3g:10 ~ 500g:9 ~ 400g:5 ~ 250g;

The condition optimization of reaction is 0 ~-50 DEG C of reaction 0.5 ~ 15h;

In addition, in step (6), can after TLC (thin-layer chromatography) detection reaction, reaction solution is poured in frozen water, add organic solvent (comprising: in ethyl acetate, methylene dichloride, methyl tertiary butyl ether etc. one or more), stir, leave standstill, separate organic layer, washing, salt solution (as saturated aqueous common salt) are washed once, concentrate to obtain product.

(7) preparation of compound 8

Under solvent, acid (acid as isomerization agent) and compound 7 react, and obtain compound 8 ((5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-oxo-5,9-methylene cyclooctene [7,8] pyridine);

Wherein, solvent comprises: one or more in methylene dichloride, chloroform, toluene, ether etc.;

Acid is preferably trifluoromethayl sulfonic acid;

The amount ratio of acid and compound 7 is preferably 10 ~ 500g:10 ~ 500g; Amount ratio as anhydrous methylene chloride, trifluoromethayl sulfonic acid and compound 7 is preferably 70 ~ 3500mL:10 ~ 500g:10 ~ 500g;

The condition optimization of reaction is 10 ~ 40 DEG C of reaction 3 ~ 10h;

In addition, in step (7), in HPLC monitoring after completion of the reaction, reaction solution can be poured in frozen water, is adjusted to pH8-9 with alkali lye, separate organic layer, use organic solvent (comprising: in ethyl acetate, methylene dichloride, methyl tertiary butyl ether etc. one or more) extraction again, merge organic layer, washing, salt is washed (as saturated common salt water washing), concentrates to obtain product.

(8) preparation of compound 9

With compound 8 for raw material, with triphenyl ethyl phosphonium bromide phosphine or triphenyl ethyl phosphonium chloride etc. as ethylization witting reagent, using highly basic as acid binding agent, obtained below-10 ~-60 DEG C and under anhydrous and oxygen-free condition.

Specifically can be as follows:

Under rare gas element (comprising: nitrogen) and solvent, ethylization witting reagent, highly basic and compound 8 react, obtain compound 9 ((5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-(Z/E) ethylidene-5,9-methylene cyclooctene [7,8] pyridine);

Wherein, solvent comprises: anhydrous tetrahydro furan THF (THF);

Ethylization witting reagent comprises: the one in triphenyl ethyl phosphonium bromide phosphine, triphenyl ethyl phosphonium chloride etc. or its mixture; Preferred triphenyl ethyl phosphonium bromide phosphorus;

Highly basic comprises: the one in n-Butyl Lithium or hexyllithium etc. or its mixture; Preferred n-Butyl Lithium;

The amount ratio of ethylization witting reagent, highly basic and compound 8 is preferably 10 ~ 200g:10 ~ 200mL:5 ~ 60g; Amount ratio as triphenyl ethyl phosphonium bromide phosphorus, anhydrous THF, n-Butyl Lithium and compound 8 is preferably 10 ~ 200g:30 ~ 700mL:10 ~ 200mL:5 ~ 60g;

The condition optimization of reaction is less than-10 ~-60 DEG C, reaction 3 ~ 10h;

In addition, in step (8), can after TLC (thin-layer chromatography) detection reaction, reaction solution is poured in frozen water, with organic solvent (comprising: in ethyl acetate, methylene dichloride, methyl tertiary butyl ether etc. one or more) extraction, washing, salt is washed (as saturated common salt water washing), concentrated, silica gel column chromatography is (as adopted 300 ~ 400 order silica gel, elutriant is the mixture of sherwood oil and ethyl acetate, wherein, the volume ratio=100:2 ~ 100:5 of sherwood oil and ethyl acetate) obtain product.

(9) preparation of compound 10

Using aprotic solvent as reaction solvent, under the initiator that radical initiator and catalytic isomerization react, react obtained through compound 9 and ordorless nontoxic thiophenol derivatives.

Specific as follows:

Under the initiator and radical initiator of aprotic solvent, catalytic isomerization reaction, compound 9 and thiophenol derivatives react, obtain compound 10 ((5R, 9R, 11E)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine);

Wherein, aprotic solvent comprises: the one in toluene or dimethylbenzene etc. or its mixture; Preferred toluene;

The initiator of catalytic isomerization reaction comprises: zinc powder;

Radical initiator comprises: one or more in Diisopropyl azodicarboxylate (AIBN) or 2,2'-Azobis(2,4-dimethylvaleronitrile) (AVBN), TEMPO (tetramethyl piperidine) etc.;

Thiophenol derivatives comprises: one or more in meta-methoxy thiophenol or 2,6-thiophenol dimethyl benzene, 2,4-thiophenol dimethyl benzenes, 3,5-dimethoxy thiophenols, 2,4-dimethoxy thiophenols etc.;

The amount ratio of the initiator that catalytic isomerization reacts, radical initiator, thiophenol derivatives and compound 9 is preferably 0.2 ~ 2g:15 ~ 150g:30 ~ 400g:10 ~ 100g; Amount ratio as dry toluene, zinc powder, radical initiator, thiophenol derivatives and compound 9 is preferably 150 ~ 1500mL:0.2 ~ 2g:15 ~ 150g:30 ~ 400g:10 ~ 100g;

The condition optimization of reaction is 30 ~ 100 DEG C of reaction 5 ~ 30h;

In addition, in step (9), can detect by HPLC, more than 95% transfer E formula to after, be cooled to room temperature, reaction solution is washed with aqueous sodium hydroxide solution, hydrochloric acid (as 10% (mass concentration) dilute hydrochloric acid) extraction of gained aprotic solvent layer, merges sour water layer, adjusts pH8-9 with aqueous sodium hydroxide solution, obtain thick white thing, use organic solvent (comprising: in ethyl acetate, methylene dichloride, methyl tertiary butyl ether etc. one or more) extraction again, washing, salt is washed (as saturated common salt water washing), drying, concentrates to obtain product.

(10) preparation of compound 11

Under solvent, compound 10 and mineral alkali react, and obtain compound 11 ((5R, 9R, 11E)-2-methoxyl group-5-carboxyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine);

Wherein, solvent comprises: one or more in the mixture, aprotic solvent etc. of water, water and protonic solvent; Described protonic solvent comprises: one or more in methyl alcohol, ethanol, Virahol, ethylene glycol monomethyl ether etc.; Aprotic solvent comprises: one or more in tetrahydrofuran (THF) (THF), dme (DME), Isosorbide-5-Nitrae-dioxane etc.; Be preferably aqueous ethanolic solution, the volume ratio being more preferably ethanol and water is preferably 90:10;

Mineral alkali comprises: one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta etc.; Preferred sodium hydroxide.

Compound 10 is preferably 1:10 ~ 1:15 with the mol ratio of mineral alkali; As compound 10 and sodium hydroxide aqueous ethanolic solution react, wherein, the concentration of sodium hydroxide in aqueous ethanolic solution is preferably 2 ~ 10mol/L, is more preferably 4 ~ 7mol/L, and compound 10 is preferably 6 ~ 60g:100 ~ 1000mL with the amount ratio of sodium hydroxide aqueous ethanolic solution;

The condition optimization of reaction is back flow reaction 1 ~ 10h;

In addition, in step (10), after reaction terminates, concentrating under reduced pressure (as removing 80% solvent), add frozen water, with organic solvent (comprising: in ethyl acetate, methylene dichloride, methyl tertiary butyl ether etc. one or more) extraction, water layer hydrochloric acid (as 20% (mass concentration) hydrochloric acid) is adjusted to pH4 ~ 6, there is a large amount of thick white thing, use organic solvent (comprising: in ethyl acetate, methylene dichloride, methyl tertiary butyl ether etc. one or more) extraction again, washing, dried over mgso, concentrated, obtain product.

(11) preparation of compound 12

At aprotic solvent or under there is not solvent, compound 11 and triethylamine and acid azid nitrogenize reagent react, obtain compound 12 ((5R, 9R, 11E)-2-methoxyl group-5-isocyanato-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine);

Wherein, aprotic solvent comprises: one or more in methylene dichloride, toluene, ethyl acetate, methyl tert-butyl ether etc.;

Acid azid nitrogenize pack is drawn together: NaN ₃or diphenyl phosphate azide (DPPA);

The mol ratio of compound 11, triethylamine and acid azid diazotizing reagent is preferably 1:3 ~ 5:2 ~ 3; Amount ratio as compound 11, triethylamine and DPPA is preferably 5 ~ 50g:6 ~ 60mL:7 ~ 70mL;

The condition optimization of reaction is 25 ~ 150 DEG C of reaction 1 ~ 15h;

In addition, in step (11), can after TLC (thin-layer chromatography) detection reaction, concentrating under reduced pressure removes partial solvent and triethylamine, obtains product.

(12) preparation of compound 13

Compound 12 and methyl alcohol react, and obtain compound 13 ((5R, 9R, 11E)-2-methoxyl group-5-methoxycarbonyl amido-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine);

Wherein, the condition optimization of reaction is back flow reaction 6 ~ 30h;

Compound 12 is preferably 1:8 ~ 1:12 with the mass ratio of methyl alcohol;

In addition, in step (12), can after TLC (thin-layer chromatography) detection reaction, pour in frozen water, organic solvent (comprising: in ethyl acetate, methylene dichloride, methyl tertiary butyl ether etc. one or more) extraction, washing, salt is washed (as saturated common salt water washing), dry, concentrating under reduced pressure, (as adopted 300 ~ 400 order silica gel, elutriant is the mixture of sherwood oil and ethyl acetate to silica gel column chromatography, wherein, the volume ratio=100:2 ~ 100:10 of sherwood oil and ethyl acetate) obtained.

(13) preparation of compound 1

In acetonitrile, compound 13 reacts with trimethylchlorosilane (TMSCl) and iodide, obtain compound 1 ((5R, 9R, 11E)-2-methoxyl group-5-methoxycarbonyl amido-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine), i.e. selagine;

Wherein, iodide comprise: the one in sodium iodide or potassiumiodide etc. or its mixture; Preferred sodium iodide;

The mol ratio of compound 13, trimethylchlorosilane (TMSCl) and iodide is preferably 1:3 ~ 6:2.5 ~ 5.5:1; Amount ratio as compound 13, acetonitrile, TMSCl and sodium iodide is preferably 10 ~ 150g:50 ~ 1000mL:10 ~ 350mL:20 ~ 400g;

The condition optimization of reaction is 25 ~ 100 DEG C of reaction 2 ~ 10h;

In addition, in step (13), can after TLC (thin-layer chromatography) detection reaction, reaction solution is poured into water, pH8-12 is adjusted to saturated solution of potassium carbonate or strong aqua, (comprising: methylene dichloride with water-insoluble non-protonic solvent, ethyl acetate, one or more in methyl tertiary butyl ether etc.) extraction, washing, salt is washed (as saturated common salt water washing), dry, concentrating under reduced pressure, obtain oily matter, oily matter acetonitrile solution (as 50% (volumetric concentration) acetonitrile solution) recrystallization is obtained crude product, gained crude product obtains sterling with ethanol water recrystallization again.

The present invention adopts be easy to get 1, 4-cyclohexanedione monoethylene acetal is starting raw material, through condensation reaction, cyclization and hydroxymethylation obtain important intermediate 2-methoxyl group-6-ethylene ketal base-5, 6, 7, 8-tetrahydroquinoline, under acidic conditions, acid hydrolysis obtains 2-methoxyl group-6-oxo-5 again, 6, 7, 8-tetrahydroquinoline, 2-methoxyl group-5-butyloxycarbonyl-6-oxo-5 is obtained by reacting with diisopropyl carbonate, 6, 7, 8-tetrahydroquinoline, this intermediate is again with 1, 3-methylene radical propylene glycol two Tricholroacetic Acid ester obtains optical homochiral intermediate (5R through asymmetric condensation reaction under the catalysis of homemade Tanaiphosligand reagent, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methylene radical-11-oxo-5, pungent and the pyridine of 9-methylene ring, again respectively by rearrangement reaction, witting reacts, chemical resolution, hydrolysis reaction, storehouse orange red this rearrangement and the reaction that is finally hydrolyzed, obtained optical homochiral selagine finished product.

The present invention instead of the condensation reaction mentioned in above-mentioned route 5 in the preparation of compound 3 by condensation and cyclization, thus instead of Methyl propiolate expensive in route 5 with vinyl cyanide comparatively cheap and easy to get, and carry out catalysis with the gas raw material ammonia that liquid reagent pyrroles and Glacial acetic acid instead of in route 5, effectively avoid high-temperature high-voltage reaction, the operability of scale operation and security are greatly improved.In next step reaction simultaneously after obtaining compound 5; we instead of methylcarbonate in route 5 as protecting group with sterically hindered larger diisopropyl carbonate; thus in this step asymmetric synthesis, effectively inhibit the generation of isomer impurities, product purity and yield are increased substantially.In addition, the chiral catalyst SL-T002-01 mentioned in route 5 only has an external Reagent Company to have sale, expensive and cannot supply in a large number, this just brings difficulty to scale operation, this route adopt more be easy to get and the comparatively cheap Tanaiphos phosphorus part of price as chiral catalyst, thus make to become possibility on a large scale.

Wherein, in step (1), easy control of reaction, solvent can recovery, and reaction yield is high; In step (2), solvent-free reaction, yield is high, environmental protection, and post-processing operation is simple; In step (5), adopt diisopropyl carbonate as reaction raw materials and innoxious solvent, the product generated can obtain the product (structure that namely products therefrom is is protecting group with sterically hindered larger sec.-propyl of high EE value in chiral synthesize below, be conducive to the generation of required chiral conformation), be conducive to the purifying of latter products and the reduction of cost; In step (6), owing to adopting homemade Tanaiphos phosphorus part, make this step chiral synthesize can obtain the product of high EE value, reduce costs further and applicable industrialization amplification; In step (9), avoid using highly toxic product thiophenol, use meta-methoxy thiophenol or spices that taste is less, 2,6-thiophenol dimethyl benzene etc. carries out cis-trans-isomer conversion and also plays same effect, makes this reaction scheme be more suitable for industrialization and amplifies.Yield does not have difference simultaneously.

In sum, the present invention with reference to above-mentioned 5 routes, and improved and optimizated on the basis of route 5, the present invention has that raw material is easy to get, easy and simple to handle, yield is higher, cost is lower, finished product purity higher (HPLC purity >=99.0%), the advantage such as easy to control the quality, is relatively applicable to suitability for industrialized production.

Embodiment

If not otherwise specified, be then commercially produced product, purity is AG to reagent involved in following examples.

In addition, the silica gel load sulfuric acid catalyst below related to is prepared according to Publication about Document:

Li Jianwei etc. the research of silica gel load sulfuric acid catalysis esterification. application chemical industry .2005,34 volumes the 6th phase, 364-365.

In addition, the self-control Tanaiphos phosphorus part related in following examples is prepared according to Publication about Document:

Tetrahedron:Asymmetry15(2004)，91-102。

Embodiment 1

(1) preparation of compound 2 (2-cyanoethyl-Isosorbide-5-Nitrae-cyclohexanedione-4-monoethylene glycol ketal)

By 650g1,4-cyclohexanedione monoethylene acetal and 300g Pyrrolidine join in 5L three-necked bottle, add 2000mL Glacial acetic acid, back flow reaction 4h, TLC raw material reaction is complete, drips 250g vinyl cyanide, backflow 12h, TLC (thin-layer chromatography) detection reaction is complete, reclaim under reduced pressure Glacial acetic acid, and gained oily matter 3000mL methyl tert-butyl ether dissolves, washing, saturated common salt water washing, dry bath, suction filtration, concentrate to obtain 2-cyanoethyl-1,4-cyclohexanedione-4-monoethylene glycol ketal 850g, yield 98%, HPLC >=95.4%.

MS (ESI) m/z210.23 [M+H] of compound 2 ⁺;

Compound 2 ¹h-MNR (300MHz, DMSO) δ ppm: δ 2.08 (2H, t, J=6.5Hz, CH ₂), δ 2.15 (2H, s, CH ₂), δ 2.27 (2H, t, J=6.5Hz, CH ₂), δ 3.95 (4H, s, CH ₂-CH ₂), δ 2.21 (1H, m, CH), δ 1.90 (2H, m, CH ₂), δ 2.41 (2H, t, J=6.3Hz, CH ₂).

(2) preparation of compound 3 (2-hydroxyl-6-ethylene ketal base-5,6,7,8-tetrahydroquinoline)

Above-mentioned for 300g 2-cyanoethyl-Isosorbide-5-Nitrae-cyclohexanedione-4-monoethylene glycol ketal and 20g silica gel load sulfuric acid catalyst are stirred, vacuumizes; nitrogen protection, 160 DEG C of stirring reaction 20h, TLC detection reaction is complete; add 500mL glycol dimethyl ether and be heated to backflow, product is entirely molten, suction filtration removing silica gel load sulfuric acid catalyst; filtrate is concentrated removes 300mL solvent, freezing crystallization, suction filtration; drying, obtains 2-hydroxyl-6-ethylene ketal base-5,6; 7,8-tetrahydroquinoline 200g, yield 67%.

MS (ESI) m/z206.24 [M-H] of compound 3 ^-;

Compound 3 ¹h-MNR (300MHz, DMSO) δ ppm: δ 1.88 (2H, t, J=6.4Hz, CH ₂), δ 2.66 (2H, s, CH ₂), δ 3.05 (2H, t, J=6.4Hz, CH ₂), δ 4.05 (4H, s, CH ₂-CH ₂), δ 6.30 (1H, d, J=9.3Hz, Ar-H), δ 7.49 (1H, d, J=9.3Hz, Ar-H), δ 11.62 (1H, s, OH).

(3) preparation of compound 4 (2-methoxyl group-6-ethylene ketal base-5,6,7,8-tetrahydroquinoline)

By above-mentioned for 180g 2-hydroxyl-6-ethylene ketal base-5,6,7,8-tetrahydroquinoline, 3g Tetrabutyl amonium bromide, 2500mL methyl tertiary butyl ether join in 5L three-necked bottle, take 40g sodium hydroxide 2000mL water dissolution, join in reaction flask, take after 240g silver carbonate adds again, stir 5min.Take 350g methyl iodide 500mL methyl tertiary butyl ether to dissolve, slowly drip, 30min dropwises.Interior temperature is between 25-35 DEG C, and the reaction of reaction 10h, TLC point plate is complete, and filter, saturated aqueous common salt washes twice, concentrated, obtains 2-methoxyl group-6-ethylene ketal base-5,6,7,8-tetrahydroquinoline 180g, yield 94%.

MS (ESI) m/z222.25 [M+H] of compound 4 ⁺;

Compound 4 ¹h-MNR (300MHz, DMSO) δ ppm: δ 2.04 (2H, t, J=7.5Hz, CH ₂), δ 2.87 (2H, s, CH ₂), δ 3.00 (2H, t, J=7.5Hz, CH ₂), δ 3.88 (3H, s, CH ₃), δ 4.02 (4H, s, CH ₂-CH ₂), δ 6.52 (1H, d, J=6.1Hz, Ar-H), δ 7.26 (1H, d, J=6.1Hz, Ar-H).

(4) preparation of compound 5 (2-methoxyl group-6-oxo-5,6,7,8-tetrahydroquinoline)

150g2-methoxyl group-6-ethylene ketal base-5,6,7,8-tetrahydroquinoline, 600mL10% (mass percent) the tosic acid aqueous solution, 0.5gTBAB, reflux 10h will be added in reaction flask.TLC point plate, reacts complete, is chilled to room temperature 4M sodium hydroxide and is adjusted to pH9, with 500mL × 2 extraction into ethyl acetate, merges organic layer, use 500mL × 2 salt water washing again, anhydrous sodium sulfate drying, suction filtration, concentrated, obtain 2-methoxyl group-6-oxo-5,6,7,8-tetrahydroquinoline 105g, yield 87%.

MS (ESI) m/z178.20 [M+H] of compound 5 ⁺;

Compound 5 ¹h-MNR (300MHz, CDCl ₃) δ ppm: δ 6.30 (1H, d, J=6.1Hz, Ar-H), δ 7.49 (1H, d, J=6.1Hz, Ar-H), δ 3.71 (2H, s, CH ₂), δ 2.78 (2H, t, J=6.0Hz, CH ₂), δ 3.16 (2H, t, J=6.0Hz, CH ₂), δ 3.80 (3H, s, CH ₃).

(5) preparation of compound 6 (2-methoxyl group-5-butyloxycarbonyl-6-oxo-5,6,7,8-tetrahydroquinoline)

In 2L three-necked bottle, add 1000ml diisopropyl carbonate and 30gNaH (60%, mass percent), under nitrogen protection condition, oil bath is heated to 110 DEG C.Above-mentioned for 100g gained 2-methoxyl group-6-oxo-5,6,7,8-tetrahydroquinoline is dissolved in 500ml diisopropyl carbonate, then the 3h that refluxes.TLC detection reaction is complete, decompression and solvent recovery, concentrated solution is poured in 1L frozen water, pH1-2 is adjusted to 10% (mass percent) hydrochloric acid, with 500mL extraction into ethyl acetate water layer, discard organic layer, water layer saturated solution of sodium carbonate is adjusted to pH9, then uses 500mL × 2 extraction into ethyl acetate.Merge organic layer, with 500mL × 2 salt water washing, anhydrous sodium sulfate drying, suction filtration, concentrated, obtain 2-methoxyl group-5-butyloxycarbonyl-6-oxo-5,6,7,8-tetrahydroquinoline 110g, yield 75%.

MS (ESI) m/z264.29 [M+H] of compound 6 ⁺;

Compound 6 ¹h-MNR (300MHz, CDCl ₃) δ ppm: δ 6.32 (1H, d, J=6.1Hz, Ar-H), δ 7.50 (1H, d, J=6.1Hz, Ar-H), δ 2.83 (2H, t, J=6.0Hz, CH ₂), δ 3.18 (2H, t, J=6.0Hz, CH ₂), δ 3.90 (3H, s, CH ₃), δ 4.47 (1H, s, CH), δ 4.93 (1H, m, CH), δ 1.32 (6H, d, J=7.4Hz, CH ₃).

(6) preparation of compound 7 ((5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methylene radical-11-oxo-5,9-methylene ring pungent and pyridine)

Add the anhydrous DME of 200ml at 1000ml three-necked bottle, nitrogen ball replaces three times, adds 25g and makes Tanaiphos phosphorus part and 0.6g diallyl Palladous chloride by oneself, stir 5min.In cooling, temperature is to-15 DEG C.83g1,3-bis-methylene propylene glycol two trichloroacetic esters and above-mentioned gained 2-methoxyl group-5-butyloxycarbonyl-6-oxo-5,6,7,8-tetrahydroquinoline 50g be dissolved in the anhydrous DME solution of 200mL, slowly drip, temperature not super-10 DEG C in cryosel bath keeps, stirs 30min.Take 80gDBU to be dissolved in the anhydrous DME of 100mL, 1h dropwises.Stir 3h again, TLC detects, and reacts complete.Reaction solution is poured in 2L frozen water, add 1000mL ethyl acetate, stir, leave standstill, separate organic layer, washing, salt washing once, concentrates to obtain (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methylene radical-11-oxo-5, pungent and the pyridine 754.0g of 9-methylene ring, yield 90%, HPLC >=98.5%.

MS (ESI) m/z316.36 [M+H] of compound 7 ⁺;

Compound 7 ¹h-MNR (300MHz, DMSO) δ ppm: δ 5.11 (1H, d, J=3.0HzCH ₂=C h ₂), δ 4.92 (1H, d, J=3.0Hz, CH ₂=C h ₂), δ 2.20 (2H, m, CH ₂), δ 2.77 (1H, m, CH), 2.88 (2H, m, CH ₂), 3.25 (2H, m, CH ₂), 3.82 (3H, s, CH ₃), 6.61 (1H, dJ=9.0Hz), 6.70 (1H, d, J=9.0Hz), δ 4.50 (1H, m, CH), δ 1.36 (6H, d, J=7.4Hz, CH ₃)

(7) preparation of compound 8 ((5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-oxo-5,9-methylene cyclooctene [7,8] pyridine)

Get 200mL anhydrous methylene chloride, add 30g trifluoromethayl sulfonic acid.Pungent for (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methylene radical-11-oxo-5,9-methylene ring and pyridine 30g 10mL anhydrous methylene chloride dissolved, be slowly added dropwise in solution, interior temperature control is at 30 DEG C, and HPLC monitors, and about 5h reacts complete.Reaction solution is poured in 500mL frozen water, be adjusted to pH8-9 with aqueous sodium hydroxide solution, separate organic layer, then use 200mL dichloromethane extraction, merge organic layer, washing, saturated common salt water washing, concentrates to obtain (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-oxo-5,9-methylene cyclooctene [7,8] pyridine 30g, yield calculates by 100%.

MS (ESI) m/z316.36 [M+H] of compound 8 ⁺;

Compound 8 ¹h-MNR (300MHz, DMSO) δ ppm: δ 1.82 (3H, s, CH ₃), δ 5.26 (1H, d, J=17Hz, CH ₂=C h ₂), δ 3.00 (2H, m, CH ₂), δ 3.04 (2H, m, CH ₂), δ 3.76 (3H, s, CH ₃), δ 3.42 (1H, m, CH), δ 6.63 (1H, d, J=9.0Hz), δ 7.45 (1H, d, J=9.0Hz), δ 4.93 (1H, m, CH), δ 1.32 (6H, d, J=7.4Hz, CH ₃).

(8) preparation of compound 9 ((5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-(Z/E) ethylidene-5,9-methylene cyclooctene [7,8] pyridine)

Get 500mL tri-bottles, add 58g triphenyl ethyl phosphonium bromide phosphorus, the anhydrous THF of 150mL, nitrogen replacement, dry ice acetone bath is chilled to less than-60 DEG C, and instillation 56mL n-Butyl Lithium, stirs 2h.Dissolve above-mentioned gained (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-oxo-5,9-methylene cyclooctene [7,8] and pyridine 20g with the anhydrous THF of 50mL, in instillation reaction solution, reaction 5h, TLC detect, and raw material reaction is complete.Reaction solution is poured in 2L frozen water, use 1L extraction into ethyl acetate, washing, saturated common salt water washing, concentrated, silica gel column chromatography (300 ~ 400 order silica gel, elutriant is the mixture of sherwood oil and ethyl acetate, wherein, the volume ratio=100:2 ~ 100:5 of sherwood oil and ethyl acetate, gradient elution) obtain (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-(Z/E) ethylidene-5,9-methylene cyclooctene [7,8] pyridine 20g, yield 97%.

MS (ESI) m/z328.42 [M+H] of compound 9 ⁺.

(9) preparation of compound 10 ((5R, 9R, 11E)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine)

Get 500mL three-necked bottle, add (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-(Z/E) ethylidene-5,9-methylene cyclooctene [7,8] and pyridine 20g, 300mL dry toluene, add 0.4g zinc powder, 26gAIBN and 70g meta-methoxy thiophenol 65 DEG C reaction 15h, HPLC detect, 95% is E formula.Be chilled to room temperature, wash reaction solution twice with 2M aqueous sodium hydroxide solution, each 100mL.Extraction is washed in toluene layer 10% (mass percent) dilute hydrochloric acid 200mL × 2 time, merges sour water layer, adjusts PH8-9 with aqueous sodium hydroxide solution, obtain thick white thing, then with ethyl acetate 200mL extraction, wash, saturated common salt water washing, drying, concentrates to obtain (5R, 9R, 11E)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine 16g, yield 80%.

MS (ESI) m/z328.42 [M+H] of compound 10 ⁺;

Compound 10 ¹h-MNR (300MHz, DMSO) δ ppm: δ 1.64 (3H, s, CH ₃), δ 5.21 (1H, s, CH ₂=C h ₂), δ 3.06 (2H, m, CH ₂), δ 2.52 (2H, m, CH ₂), δ 3.80 (3H, s, CH ₃), δ 3.24 (1H, m, CH), δ 6.61 (1H, d, J=9.1Hz, Ar-H), δ 7.49 (1H, d, J=9.1Hz, Ar-H), δ 4.95 (1H, m, CH), δ 1.33 (6H, d, J=7.4Hz, CH ₃), 5.29 (1H, m, CH ₂=C h ₂), 2.05 (3H, d, J=6.6Hz, CH ₃).

(10) preparation of compound 11 ((5R, 9R, 11E)-2-methoxyl group-5-carboxyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine)

By (5R, 9R, 11E)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] and pyridine 12g, add 6M sodium hydroxide aqueous ethanolic solution (ethanol: the volume ratio=90:10 of water) 200mL, be warming up to backflow, 3h hydrolysis is complete.Concentrating under reduced pressure removes 80% solvent, adds 300mL water, and with 100mL × 2 dichloromethane extraction, water layer is adjusted to PH4 with 20% (mass percent) hydrochloric acid a large amount of thick white thing.With 300mL × 2 dichloromethane extraction, merge organic layer, washing twice, dried over mgso, concentrated, obtain (5R, 9R, 11E)-2-methoxyl group-5-carboxyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] and pyridine 10g, yield 95%.

MS (ESI) m/z284.34 [M+H] of compound 11 ^-.

Compound 11 ¹h-MNR (300MHz, DMSO) δ ppm: δ 1.67 (3H, s, CH ₃), δ 5.23 (1H, s, CH ₂=C h ₂), δ 3.07 (2H, m, CH ₂), δ 2.54 (2H, m, CH ₂), δ 3.81 (3H, s, CH ₃), δ 3.24 (1H, m, CH), δ 6.64 (1H, d, J=9.1Hz, Ar-H), δ 7.50 (1H, d, J=9.1Hz, Ar-H), 5.32 (1H, m, CH ₂=C h ₂), 2.00 (3H, d, J=6.5Hz, CH ₃).

(11) preparation of compound 12 ((5R, 9R, 11E)-2-methoxyl group-5-isocyanato-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine)

By (5R, 9R, 11E)-2-methoxyl group-5-carboxyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine 20g, triethylamine 35mL and DPPA40mL join in three-necked bottle, then add anhydrous methylene chloride 100mL, stirring at room temperature 1h, back flow reaction 15h.TLC detection reaction is complete, and concentrating under reduced pressure removes methylene dichloride and triethylamine, obtains product, not purifiedly directly does the next step.

(12) preparation of compound 13 ((5R, 9R, 11E)-2-methoxyl group-5-methoxycarbonyl amido-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine)

Upper step reaction solution is added 300mL methanol eddy 12h, TLC point plate reacts completely, pour in 2000mL water, with 500mL × 2 dichloromethane extraction, washing, saturated common salt water washing, dry, concentrating under reduced pressure, silica gel column chromatography (300 ~ 400 order silica gel, elutriant is the mixture of sherwood oil and ethyl acetate, wherein, volume ratio=100:2 ~ the 100:10 of sherwood oil and ethyl acetate, gradient elution), obtain (5R, 9R, 11E)-2-methoxyl group-5-methoxycarbonyl amido-7-methyl isophthalic acid 1-ethylidene-5, 9-methylene cyclooctene [7, 8] and pyridine 18.7g, yield 85%.

MS (ESI) m/z315.38 [M+H] of compound 13 ⁺.

(13) preparation of finished product compound 1---selagine ((-)-HuperzineA)

By (5R, 9R, 11E)-2-methoxyl group-5-methoxycarbonyl amido-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] and pyridine 10g and sodium iodide 25g join in three-necked bottle, then add 20mLTMSCl and 50mL acetonitrile, stirring at room temperature 0.5h, temperature rising reflux 4 ~ 8 hours again, TLC detection reaction is complete.Concentrating under reduced pressure partial solvent, gained oily matter is poured in 300mL frozen water, first use 100mL extraction into ethyl acetate, gained water layer ammoniacal liquor is adjusted to pH9-10, separate out white solid, extract with methylene dichloride 100mL × 3, merge organic layer, washing, saturated common salt water washing, dry, concentrating under reduced pressure, obtains oily matter 7g, oily matter 25mL50% (volume percent) acetonitrile solution recrystallization, gained solid obtains (-)-HuperzineA5g (HPLC purity is 99.3%) with aqueous ethanolic solution recrystallization again, yield 65%.

MS (ESI) m/z241.32 [M+H] of selagine ⁺;

Selagine ¹h-MNR (400MHz, CDCl ₃) δ ppm: δ 13.1 (1H, s, OH), δ 7.90 (1H, d, J=9.6Hz, Ar-H), δ 6.41 (1H, d, J=9.6Hz, Ar-H), δ 5.41 (1H, s, CH ₂=C h ₂), 5.47 (1H, q, J=6.7Hz, CH ₂=C h ₂), δ 3.60 (1H, m, CH), δ 2.75 (2H, m, CH ₂), δ 2.12 (2H, d, J=4.0Hz, CH ₂), δ 1.66 (3H, d, J=6.8Hz, CH ₃), δ 1.53 (3H, s, CH ₃).

Embodiment 2

400g1,4-cyclohexanedione monoethylene acetal and 185g Pyrrolidine are joined in 5L three-necked bottle, adds 2000mL Glacial acetic acid, back flow reaction 5h, TLC raw material reaction is complete, drips 155g vinyl cyanide, backflow 20h, TLC detection reaction is complete, reclaim under reduced pressure Glacial acetic acid, gained oily matter 2000mL methyl tert-butyl ether dissolves, washing, saturated common salt water washing, dry bath, suction filtration, concentrates to obtain 2-cyanoethyl-1,4-cyclohexanedione-4-monoethylene glycol ketal 520g, yield 96%.

Above-mentioned for 200g 2-cyanoethyl-Isosorbide-5-Nitrae-cyclohexanedione-4-monoethylene glycol ketal and 15g silica gel load sulfuric acid catalyst are stirred, vacuumizes; nitrogen protection, 170 DEG C of stirring reaction 20h, TLC detection reaction is complete; add 400mL glycol dimethyl ether and be heated to backflow, product is entirely molten, suction filtration removing silica gel load sulfuric acid catalyst; filtrate is concentrated removes 200mL solvent, freezing crystallization, suction filtration; drying, obtains 2-hydroxyl-6-ethylene ketal base-5,6; 7,8-tetrahydroquinoline 120g, yield 60%.

By above-mentioned for 100g 2-hydroxyl-6-ethylene ketal base-5,6,7,8-tetrahydroquinoline, 2g Tetrabutyl amonium bromide, 2000mL methyl tertiary butyl ether join in 5L three-necked bottle, take 31g sodium hydroxide 1200mL water dissolution, join in reaction flask, take after 140g silver carbonate adds again, stir 10min.Take 200g methyl iodide 300mL methyl tertiary butyl ether to dissolve, slowly drip, 30min dropwises.Interior temperature is between 25-35 DEG C, and the reaction of reaction 15h, TLC point plate is complete, and filter, saturated aqueous common salt washes twice, concentrated, obtains 2-methoxyl group-6-ethylene ketal base-5,6,7,8-tetrahydroquinoline 95g, yield 90%.

100g2-methoxyl group-6-ethylene ketal base-5,6,7,8-tetrahydroquinoline will be added, 400mL10% (mass percent) the tosic acid aqueous solution, 0.5gTBAB, reflux 15h in reaction flask.TLC point plate, reacts complete, is chilled to room temperature 4M sodium hydroxide and is adjusted to pH9, with 500mL × 2 extraction into ethyl acetate, merges organic layer, use 500mL × 2 salt water washing again, anhydrous sodium sulfate drying, suction filtration, concentrated, obtain 2-methoxyl group-6-oxo-5,6,7,8-tetrahydroquinoline 72g, yield 90%.

In 2L three-necked bottle, add 600ml diisopropyl carbonate and 20gNaH (60%), under nitrogen protection condition, oil bath is heated to 105 DEG C.Above-mentioned for 65g gained 2-methoxyl group-6-oxo-5,6,7,8-tetrahydroquinoline is dissolved in 200ml diisopropyl carbonate, backflow 5h.TLC detection reaction is complete, decompression and solvent recovery, concentrated solution is poured in 1L frozen water, pH1-2 is adjusted to 10% (mass percent) hydrochloric acid, with 500mL extraction into ethyl acetate water layer, discard organic layer, water layer saturated solution of sodium carbonate is adjusted to pH9, then uses 500mL × 2 extraction into ethyl acetate.Merge organic layer, with 500mL × 2 salt water washing, anhydrous sodium sulfate drying, suction filtration, concentrated, obtain 2-methoxyl group-5-butyloxycarbonyl-6-oxo-5,6,7,8-tetrahydroquinoline 76g, yield 80%.

Add the anhydrous DME of 300ml at 1000ml three-necked bottle, nitrogen ball replaces three times, adds 30g and makes Tanaiphos phosphorus part and 0.7g diallyl Palladous chloride by oneself, stir 5min.In cooling, temperature is to-20 DEG C.100g1,3-bis-methylene propylene glycol two trichloroacetic esters and above-mentioned gained 2-methoxyl group-5-butyloxycarbonyl-6-oxo-5,6,7,8-tetrahydroquinoline 50g be dissolved in the anhydrous DME solution of 200mL, slowly drip, temperature not super-20 DEG C in cryosel bath keeps, stirs 30min.Take 73gDBU to be dissolved in the anhydrous DME of 100mL, 1h dropwises.Stir 3h again, TLC detects, and reacts complete.Reaction solution is poured in 2L frozen water, add 1000mL ethyl acetate, stir, leave standstill, separate organic layer, washing, salt washing once, concentrates to obtain (5R, 9R) the pungent and pyridine 61g of-2-methoxyl group-5-butyloxycarbonyl-7-methylene radical-11-oxo-5,9-methylene ring, yield 85%.EE value is 98.

Get 200mL anhydrous methylene chloride, add 30g trifluoromethayl sulfonic acid.Pungent for (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methylene radical-11-oxo-5,9-methylene ring and pyridine 50g 30mL anhydrous methylene chloride dissolved, be slowly added dropwise in solution, interior temperature control is at 25 DEG C, and HPLC monitors, and about 8h reacts complete.Reaction solution is poured in 500mL frozen water, be adjusted to pH8-9 with aqueous sodium hydroxide solution, separate organic layer, then use 500mL dichloromethane extraction, merge organic layer, washing, saturated common salt water washing, concentrates to obtain (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-oxo-5,9-methylene cyclooctene [7,8] pyridine 30g, yield calculates by 100%.

Get 1000mL tri-bottles, add 100g triphenyl ethyl phosphonium bromide phosphorus, the anhydrous THF of 300mL, nitrogen replacement, dry ice acetone bath is chilled to less than-70 DEG C, and instillation 100mL n-Butyl Lithium, stirs 2h.Dissolve above-mentioned gained (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-oxo-5,9-methylene cyclooctene [7,8] and pyridine 35g with the anhydrous THF of 100mL, in instillation reaction solution, reaction 4h, TLC detect, and raw material reaction is complete.Reaction solution is poured in 2L frozen water, use 1L extraction into ethyl acetate, washing, saturated common salt water washing, concentrated, silica gel column chromatography (300 ~ 400 order silica gel, elutriant is the mixture of sherwood oil and ethyl acetate, wherein, and the volume ratio=100:2 ~ 100:5 of sherwood oil and ethyl acetate, gradient elution), obtain (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-(Z/E) ethylidene-5,9-methylene cyclooctene [7,8] and pyridine 32g, yield 90%.

Get 500mL three-necked bottle, add (5R, 9R)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-(Z/E) ethylidene-5,9-methylene cyclooctene [7,8] pyridine 30g, 300mL dry toluene, add 0.5g zinc powder, 26gAIBN and 80g meta-methoxy thiophenol 65 DEG C reaction 20h, HPLC detect, and 95% is E formula.Be chilled to room temperature, wash reaction solution twice with 2M aqueous sodium hydroxide solution, each 100mL.Extraction is washed in toluene layer 10% (mass percent) dilute hydrochloric acid 200mL × 2 time, merges sour water layer, adjusts pH8-9 with aqueous sodium hydroxide solution, obtain thick white thing, then with ethyl acetate 200mL extraction, wash, saturated common salt water washing, drying, concentrates to obtain (5R, 9R, 11E)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine 25g, yield 85%.

By (5R, 9R, 11E)-2-methoxyl group-5-butyloxycarbonyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] and pyridine 20g, add 6M sodium hydroxide aqueous ethanolic solution (ethanol: the volume ratio=90:10 of water) 300mL, be warming up to backflow, 4h hydrolysis is complete.Concentrating under reduced pressure removes 80% solvent, adds 250mL water, and with 100mL × 2 dichloromethane extraction, water layer is adjusted to PH4 with 20% (mass percent) hydrochloric acid a large amount of thick white thing.With 300mL × 2 dichloromethane extraction, merge organic layer, washing twice, dried over mgso, concentrated, obtain (5R, 9R, 11E)-2-methoxyl group-5-carboxyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] pyridine 15.8g, yield 90%.

By (5R, 9R, 11E)-2-methoxyl group-5-carboxyl-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] and pyridine 50g, triethylamine 90mL and DPPA100mL join in three-necked bottle, stirring at room temperature 1h, back flow reaction 2 ~ 6h.TLC detection reaction is complete, and concentrating under reduced pressure removes triethylamine, obtains product, not purifiedly directly does the next step.

Upper step reaction solution is added 1000mL methanol eddy 12h, TLC point plate reacts completely, concentrating under reduced pressure 600mL solvent, oily matter is poured in 2000mL water, with 500mL × 2 dichloromethane extraction, washing, saturated common salt water washing, dry, concentrating under reduced pressure, silica gel column chromatography (300 ~ 400 order silica gel, elutriant is the mixture of sherwood oil and ethyl acetate, wherein, volume ratio=100:2 ~ the 100:10 of sherwood oil and ethyl acetate, gradient elution), obtain (5R, 9R, 11E)-2-methoxyl group-5-methoxycarbonyl amido-7-methyl isophthalic acid 1-ethylidene-5, 9-methylene cyclooctene [7, 8] and pyridine 44g, two step yields 80%.

MS (ESI) m/z315.38 [M+H] of compound 13 ⁺.

(13) preparation of finished product (-)-HuperzineA

By (5R, 9R, 11E)-2-methoxyl group-5-methoxycarbonyl amido-7-methyl isophthalic acid 1-ethylidene-5,9-methylene cyclooctene [7,8] and pyridine 50g and sodium iodide 100g join in three-necked bottle, then drip 100mLTMSCl under adding 250mL acetonitrile ice-water bath condition, dropwise stirring at room temperature 1h, temperature rising reflux 3 ~ 9 hours again, TLC detection reaction is complete.Concentrating under reduced pressure partial solvent, gained oily matter is poured in 1000mL frozen water, first use 200mL extraction into ethyl acetate, gained water layer ammoniacal liquor is adjusted to pH9-10, separate out white solid, extract with ethyl acetate 300mL × 3, merge organic layer, washing, saturated common salt water washing, dry, concentrating under reduced pressure, obtains oily matter 37g, oily matter 80mL50% (volume percent) acetonitrile solution recrystallization, gained solid obtains (-)-HuperzineA27g (HPLC purity is 99.3%) with aqueous ethanolic solution recrystallization again, yield 70%.

MS (ESI) m/z241.32 [M+H] of (-)-HuperzineA ⁺;

(-)-HuperzineA's ¹h-MNR (400MHz, CDCl ₃) δ ppm: δ 13.1 (1H, s, OH), δ 7.90 (1H, d, J=9.6Hz, Ar-H), δ 6.41 (1H, d, J=9.6Hz, Ar-H), δ 5.41 (1H, s, CH ₂=CH ₂), 5.47 (1H, q, J=6.7Hz, CH ₂=CH ₂), δ 3.60 (1H, m, CH), δ 2.75 (2H, m, CH ₂), δ 2.12 (2H, d, J=4.0Hz, CH ₂), δ 1.66 (3H, d, J=6.8Hz, CH ₃), δ 1.53 (3H, s, CH ₃).

Claims

1. a synthetic method for selagine, is characterized in that, comprises step:

(1) preparation of compound 2

After the reaction of Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal, Pyrrolidine and Glacial acetic acid, add vinyl cyanide and react again, obtain compound 2;

(2) preparation of compound 3

Under an inert gas, compound 2 and silica gel load sulfuric acid catalyst react, and obtain compound 3;

(3) preparation of compound 4

In the mixed system of water and water-insoluble organic solvent, mineral alkali, phase-transfer catalyst and water soluble silver salt, compound 3 and methylating reagent react, and obtain compound 4;

(4) preparation of compound 5

Under phase-transfer catalyst, compound 4 and acidic aqueous solution react, and obtain compound 5;

(5) preparation of compound 6

Under an inert gas, compound 5 reacts with diisopropyl carbonate and highly basic, obtains compound 6;

Wherein, highly basic comprises: the one in sodium hydride or potassium hydride KH or its mixture;

(6) preparation of compound 7

Under rare gas element, aprotic solvent, Tanaiphos phosphorus part, palladium catalyst and organic bases exist, 1,3-bis-methylene propylene glycol two trichloroacetic esters and compound 6 react, and obtain compound 7;

(7) preparation of compound 8

Under solvent, acid and compound 7 react, and obtain compound 8; Wherein, solvent comprises: one or more in methylene dichloride, chloroform, toluene, ether;

(8) preparation of compound 9

Under rare gas element and solvent, ethylization witting reagent, highly basic and compound 8 react, and obtain compound 9;

Wherein, solvent comprises: anhydrous tetrahydro furan;

Ethylization witting reagent comprises: the one in triphenyl ethyl phosphonium bromide phosphine, triphenyl ethyl phosphonium chloride or its mixture;

Highly basic comprises: the one in n-Butyl Lithium or hexyllithium or its mixture;

(9) preparation of compound 10

Under the initiator and radical initiator of aprotic solvent, catalytic isomerization reaction, compound 9 and thiophenol derivatives react, and obtain compound 10;

Wherein, the initiator of catalytic isomerization reaction comprises: zinc powder;

(10) preparation of compound 11

Under solvent, compound 10 and mineral alkali react, and obtain compound 11;

Wherein, solvent comprises: one or more in the mixture of water, water and protonic solvent, aprotic solvent;

(11) preparation of compound 12

At aprotic solvent or under there is not solvent, compound 11 and triethylamine and acid azid nitrogenize reagent react, obtain compound 12;

(12) preparation of compound 13

Compound 12 and methyl alcohol react, and obtain compound 13;

(13) preparation of compound 1

In acetonitrile, compound 13 reacts with trimethylchlorosilane and iodide, obtains selagine.

2. the method for claim 1, it is characterized in that: in described step (1), the amount ratio of Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal, Pyrrolidine, Glacial acetic acid and vinyl cyanide is 200 ~ 1000g:90 ~ 460g:500 ~ 5000mL:80 ~ 400g; Reaction conditions is: Isosorbide-5-Nitrae-cyclohexanedione monoethylene acetal, Pyrrolidine and Glacial acetic acid back flow reaction 3 ~ 20h, drips vinyl cyanide back flow reaction 10 ~ 30h again;

In step (2), compound 2 is 100 ~ 500:5 ~ 40 with the weight ratio of silica gel load sulfuric acid catalyst; The condition of reaction is 100 ~ 200 DEG C of reaction 10 ~ 40h;

In step (3), water-insoluble organic solvent comprises: one or more in methylene dichloride, methyl tertiary butyl ether, toluene; The mixed volume ratio of water and water-insoluble organic solvent is 1:2 ~ 1:5; Mineral alkali comprises: one or more in sodium hydroxide or potassium hydroxide, lithium hydroxide, hydrated barta; Phase-transfer catalyst comprises: tetrabutyl phosphonium bromide is by, one or more in benzyltriethylammoinium chloride, benzyl trimethyl ammonium chloride, benzyl tributyl ammonium chloride, 4-propyl ammonium chloride; Water soluble silver salt comprises: the one in silver carbonate, Silver monoacetate or its mixture; Methylating reagent comprises: the one in methyl iodide, monobromethane or its mixture; The mol ratio of mineral alkali, phase-transfer catalyst, compound 3, water soluble silver salt and methylating reagent is 1 ~ 1.5:0.2 ~ 0.5:1:0.5 ~ 1; The condition of reaction is 20 ~ 35 DEG C of reaction 5 ~ 20h;

In step (4), phase-transfer catalyst comprises: tetrabutyl phosphonium bromide is by, one or more in benzyltriethylammoinium chloride, benzyl trimethyl ammonium chloride, benzyl tributyl ammonium chloride, 4-propyl ammonium chloride; Acidic aqueous solution comprises: the tosic acid aqueous solution; The amount ratio of compound 4, acidic aqueous solution and phase-transfer catalyst is 50 ~ 600g:200 ~ 3000mL:0.5 ~ 10g; The condition of reaction is back flow reaction 8 ~ 20h;

In step (5), the amount ratio of compound 5, diisopropyl carbonate and highly basic is 50 ~ 300g:500 ~ 3000mL:15 ~ 90g; The condition of reaction is 50 ~ 120 DEG C of reaction 0.5 ~ 8h;

In step (6), aprotic solvent comprises: one or more in acetone, dme, methylene dichloride, chloroform, tetrahydrofuran (THF); Palladium catalyst comprises: diallyl Palladous chloride, four triphenyl phosphorus palladiums, (dppf) ₂pdCl ₂in one or more; Organic bases comprises: one or more in 1,8-diazacyclo [5,4,0] hendecene-7, tetramethyl guanidine, pyridine, triethylamine and 4-N, N-Dimethylamino pyridine; The mol ratio of Tanaiphos phosphorus part, palladium catalyst, organic bases, 1,3-bis-methylene propylene glycol two trichloroacetic esters and compound 6 is 0.02 ~ 0.04:0.01 ~ 0.02:2 ~ 3:1 ~ 1.5:1; The condition of reaction is 0 ~-50 DEG C of reaction 0.5 ~ 15h;

In step (7), acid is trifluoromethayl sulfonic acid; The amount ratio of acid and compound 7 is 10 ~ 500g:10 ~ 500g; The condition of reaction is 10 ~ 40 DEG C of reaction 3 ~ 10h;

In step (8), the amount ratio of ethylization witting reagent, highly basic and compound 8 is 10 ~ 200g:10 ~ 200mL:5 ~ 60g; The condition of reaction is less than-10 ~-60 DEG C, reaction 3 ~ 10h;

In step (9), aprotic solvent comprises: the one in toluene or dimethylbenzene or its mixture; Radical initiator comprises: one or more in Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile), tetramethyl piperidine; Thiophenol derivatives comprises: one or more in meta-methoxy thiophenol or 2,6-thiophenol dimethyl benzene, 2,4-thiophenol dimethyl benzenes, 3,5-dimethoxy thiophenols, 2,4-dimethoxy thiophenols; The amount ratio of the initiator that catalytic isomerization reacts, radical initiator, thiophenol derivatives and compound 9 is: 0.2 ~ 2g:15 ~ 150g:30 ~ 400g:10 ~ 100g; The condition of reaction is 30 ~ 100 DEG C of reaction 5 ~ 30h;

In step (10), protonic solvent comprises: one or more in methyl alcohol, ethanol, Virahol, ethylene glycol monomethyl ether; Aprotic solvent comprises: one or more in tetrahydrofuran (THF), dme, Isosorbide-5-Nitrae-dioxane; Mineral alkali comprises: one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta; Compound 10 is 1:10 ~ 1:15 with the mol ratio of mineral alkali; The condition of reaction is back flow reaction 1 ~ 10h;

In step (11), aprotic solvent comprises: one or more in methylene dichloride, toluene, ethyl acetate, methyl tert-butyl ether; Acid azid nitrogenize pack is drawn together: NaN ₃or diphenyl phosphate azide; The mol ratio of compound 11, triethylamine and acid azid diazotizing reagent is 1:3 ~ 5:2 ~ 3; The condition of reaction is 25 ~ 150 DEG C of reaction 1 ~ 15h;

In step (12), compound 12 is 1:8 ~ 1:12 with the mass ratio of methyl alcohol; The condition of reaction is back flow reaction 6 ~ 30h;

In step (13), iodide comprise: the one in sodium iodide or potassiumiodide or its mixture; The mol ratio of compound 13, trimethylchlorosilane and iodide is 1:3 ~ 6:2.5 ~ 5.5:1; The condition of reaction is 25 ~ 100 DEG C of reaction 2 ~ 10h.

3. the method for claim 1, it is characterized in that: in described step (1), after thin-layer chromatography detection reaction, reclaim under reduced pressure Glacial acetic acid, gained oily matter water-insoluble organic solvent dissolves, washing, saturated common salt water washing, dry bath, suction filtration, concentrated obtaining product, wherein, water-insoluble organic solvent comprises: one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether;

In step (2), after thin-layer chromatography detection reaction, add glycol dimethyl ether and be heated to backflow, suction filtration silica gel load sulfuric acid catalyst, filtrate concentrates, freezing crystallization, suction filtration, dry, obtains product;

In step (3), after thin-layer chromatography detection reaction, filter, saturated aqueous common salt washes twice, concentrated, obtains product;

In step (4), after thin-layer chromatography detection reaction, be cooled to room temperature, pH9-12 is adjusted to alkali, use organic solvent extraction again, merge organic layer, saturated common salt water washing, dry, suction filtration, concentrated, obtain product, wherein, organic solvent comprises: one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether;

In step (5), after thin-layer chromatography detection reaction, concentrating under reduced pressure, concentrated solution is poured in frozen water, be adjusted to pH1-2 with hydrochloric acid, use organic solvent extraction water layer, discard organic layer, water layer saturated solution of sodium carbonate is adjusted to pH7-10, then uses organic solvent extraction, merge organic layer, saturated common salt water washing, dry, suction filtration, concentrated, obtain product, wherein, organic solvent comprises: one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether;

In step (6), after thin-layer chromatography detection reaction, reaction solution is poured in frozen water, add organic solvent, stir, leave standstill, separate organic layer, washing, saturated common salt washing once, concentrate to obtain product, wherein, organic solvent comprises: one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether;

In step (7), after HPLC detection reaction, reaction solution is poured in frozen water, be adjusted to pH8-9 with alkali lye, separate organic layer, use organic solvent extraction again, merge organic layer, washing, saturated common salt water washing, concentrated obtaining product, wherein, organic solvent comprises: one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether;

In step (8), after thin-layer chromatography detection reaction, reaction solution is poured in frozen water, with organic solvent extraction, washing, saturated common salt water washing, concentrated, silica gel column chromatography obtains product, and wherein, organic solvent comprises: one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether;

In step (9), with HPLC detect, more than 95% transfer E formula to after, be cooled to room temperature, wash reaction solution with aqueous sodium hydroxide solution, gained aprotic solvent layer hcl as extraction agent, merge sour water layer, adjust pH8-9 with aqueous sodium hydroxide solution, then use organic solvent extraction, washing, saturated common salt water washing, dry, concentrate to obtain product, wherein, organic solvent comprises: one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether;

In step (10), after reaction terminates, concentrating under reduced pressure, add frozen water, with organic solvent extraction, water layer hydrochloric acid is adjusted to pH4 ~ 6, then uses organic solvent extraction, washing, drying, concentrated, obtain product, wherein, organic solvent comprises: one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether;

In step (11), after thin-layer chromatography detection reaction, concentrating under reduced pressure, obtains product;

In step (12), after thin-layer chromatography detection reaction, pour in frozen water, organic solvent extraction, washing, saturated common salt water washing, drying, concentrating under reduced pressure, silica gel column chromatography obtains, wherein, organic solvent comprises: one or more in ethyl acetate, methylene dichloride, methyl tertiary butyl ether;

In step (13), after thin-layer chromatography detection reaction, reaction solution is poured into water, pH8-12 is adjusted to saturated solution of potassium carbonate or strong aqua, extract with water-insoluble non-protonic solvent, washing, saturated common salt water washing, drying, concentrating under reduced pressure, obtains oily matter, oily matter acetonitrile solution recrystallization is obtained crude product, gained crude product obtains sterling with ethanol water recrystallization again, and wherein, water-insoluble non-protonic solvent comprises: one or more in methylene dichloride, ethyl acetate, methyl tertiary butyl ether.

4. the method for claim 1, is characterized in that: in described step (3), and the mixed volume ratio of water and water-insoluble organic solvent is 1:2;

Mineral alkali is sodium hydroxide;

Water soluble silver salt is silver carbonate;

Methylating reagent is methyl iodide.

5. the method for claim 1, is characterized in that: in described step (4), acidic aqueous solution to be mass concentration be 5 ~ 50% the tosic acid aqueous solution.

6. method as claimed in claim 5, is characterized in that: described acidic aqueous solution to be mass concentration be 10% the tosic acid aqueous solution.

7. the method for claim 1, is characterized in that: in described step (5), and highly basic is sodium hydride.

In step (6), aprotic solvent is dme; Palladium catalyst is diallyl Palladous chloride;

In step (8), highly basic is n-Butyl Lithium;

In step (9), aprotic solvent is toluene.

8. the method for claim 1, is characterized in that: in described step (10), and solvent is aqueous ethanolic solution, and alkali is sodium hydroxide.

9. method as claimed in claim 8, it is characterized in that: in described aqueous ethanolic solution, the volume ratio of ethanol and water is 90:10; The concentration of sodium hydroxide in aqueous ethanolic solution is 2 ~ 10mol/L.

10. method as claimed in claim 9, is characterized in that: the concentration of described sodium hydroxide in aqueous ethanolic solution is 4 ~ 7mol/L.