CN101333190A - Asymmetric synthesis for chiral huperzine A - Google Patents
Asymmetric synthesis for chiral huperzine A Download PDFInfo
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- CN101333190A CN101333190A CNA2008101329222A CN200810132922A CN101333190A CN 101333190 A CN101333190 A CN 101333190A CN A2008101329222 A CNA2008101329222 A CN A2008101329222A CN 200810132922 A CN200810132922 A CN 200810132922A CN 101333190 A CN101333190 A CN 101333190A
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Abstract
Disclosed is an asymmetric total-synthesis method for chiral huperzine a. The method takes 1,4-dihydro-spiro (4,5) -8 -decanone as starting material to get benzoate through hydroxymethylation and the treatment of benzoyl chloride and K2CO3; the benzoate is reacted with hydrogen sulfate O-methyl iso urea to get quinazoline; after the ketal is eliminated, Mander reagent is used for methyl esterification reaction so as to obtain beta-keto ester. Chiral ammonia, such as cinchona alkaloid, is used to promote the tandem asymmetric Michael addition/aldol condensation reaction of beta-keto esters and methyl acrolein. The compound carboxylate of diastereoisomer is reacted with MsCl, triethylamine and DMAP to get transformed. Through TMSI and MeOH processing, the protective group is removed so as to obtain optically pure-chiral huperzine a.
Description
Technical field
The invention belongs to the natural product technical field of organic synthesis, be specially (-)-manufacture method of selagine.
Background of invention
Selagine [(-)-Huperzine A, 1] being the alkaloid that separates the new texture that obtains from the phenol of lycopsid Herba Lycopodii serrati [Huperzia serrata (Thunb) Trev.] part, is a kind of acetylcholinesterase (AchE) inhibitor of potent, single-minded, reversible, highly selective.The clinical Therapy for Myasthemia Gravis that is mainly used in, it can improve senile memory function and go down, can significantly improve Alzheimer (Alzheimer ' s disease, AD) patient's memory, cognition and behavioral function find no tangible untoward reaction.Pharmacological evaluation shows, selagine is respectively 3 times of Physostigmine to the restraining effect of external acetylcholinesterase, 30 times of lycoremine.
The present invention relates to a kind of acetylcholinesterase depressant, more particularly, relating to natural product is the method for asymmetric synthesis of optical activity (-)-selagine.(-)-selagine chemical name is: (-)-(5R, 9R, 11E)-and 5-amino-11-ethylidene-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring cycloocta--2 (1H)-pyridone.Structural formula is as follows.
Selagine is that the gloomy people of grade of the Liu Jia of Shanghai medicine institute of the Chinese Academy of Sciences separates the alkaloid that obtains in the Chinese medicine Herba Lycopodii serrati.Herba Lycopodii serrati is Chinese distinctive plant, and the content of selagine in Herba Lycopodii serrati only is about 0.01%.The Herba Lycopodii serrati growth cycle reaches 8～10 years, and the raw material sources difficulty is extracted loaded down with trivial details hardships of operation and cost too high (about 1kg/100～1,200,000 yuans).Along with the aggravation of world population aging and urgent day by day to the pharmaceutical requirements of treatment senile dementia, the study on the synthesis of selagine becomes the hot subject of Pharmaceutical Chemist.
Because natural selagine, i.e. the activity of (-)-selagine or optical activity selagine is 38 times of its enantiomorph, thereby the synthesis of optically active selagine causes people's very big concern naturally.Representative (-)-huperzine alkali first method of asymmetric synthesis is as follows:
1991, reported first such as Kozikowski and in 1997 (US 566344 at United States Patent (USP) with calendar year 2001, US 6271379) in the method that adopts of synthesis of optically active selagine be, 'beta '-ketoester and (-)-8-phenyl menthol are carried out transesterification reaction, obtain chiral ester, carry out asymmetric Michael-aldol reaction as substrate and Methylacrylaldehyde again, obtain the bridged ring product, eliminate reaction again after becoming methanesulfonates, obtain non-enantiomer mixture, through chromatographic separation, Wittig reaction and isomerization reaction, the ester that obtains is sterically hindered very big, can not be hydrolyzed into corresponding acid, need to obtain through lithium aluminium hydride reduction and Jones oxidation.Synthesis step according to the racemize selagine obtains natural selagine then.This method (-)-8-phenyl menthol large usage quantity and reactions steps are tediously long, and the productive rate religion is low.
Nineteen ninety-five; Chen Wei equality has been reported the method for asymmetric synthesis of part optical activity selagine; with 4-oxo heptanedioic acid dimethyl ester is starting raw material; reaction forms enamine with tetramethyleneimine under titanium tetrachloride catalysis; direct then and propine acid amides reaction obtains pyridone, obtains 'beta '-ketoester through protection and intramolecularly Dieckmann condensation reaction again.Under the catalysis of 10mol% chiral base quinine, 'beta '-ketoester and Methylacrylaldehyde carry out asymmetric Michael-aldol reaction, obtain the bridged ring product, the reelimination methanesulfonates obtains the compound carboxylate methyl ester after becoming methanesulfonates, obtain the carboxylate methyl ester of 65%ee then through recrystallization, set out thus, it is complete synthesis to have finished part optical activity selagine again.
Summary of the invention
The present invention divides two portions, and first part is the synthetic of intermediate 'beta '-ketoester, and second section is the asymmetric complete synthesis of (-)-selagine.
Synthesizing with 1 of 'beta '-ketoester, 4-dihydro spiral shell [4,5]-8-decanone is a parent material, reacts 10h with ammonia methyl alcohol saturated solution and propynoic acid methyl esters down at 100 ℃, and a step obtains pyridone (2), uses methyl iodide and Ag again
2CO
3Handle, obtain ketal (3), (3) carry out esterification reaction of organic acid with KH and methylcarbonate, obtain 'beta '-ketoester (4), productive rate 89%.
In order to obtain a large amount of optical purity (-)-selagines and to have the homologue of pharmaceutical use.The invention provides the novel method of synthetic (-)-selagine of a kind of stereoselectivity, this method is more effective and practical than Kozikowski method.Synthetic method of the present invention relates to uses chirality ammonia, and for example the quinine Alkaloid promotes the file asymmetric michael addition/aldolisation of 'beta '-ketoester (4) and Methylacrylaldehyde, has good enantioselectivity (maximum enantiomeric excess 64%).Specifically be, under the existence of quinine Alkaloid as (-)-cinchovatin (1 equivalent), react, obtain (5) with 'beta '-ketoester (4) 1 equivalents and Methylacrylaldehyde 10 equivalents.Wherein, asymmetric michael addition/aldolisation pattern may be as Fig. 2.
Available quinine Alkaloid has (-)-quinine, (+)-Quinidine, (+)-cinchonine, (+)-two hydrogen cinchonines and (-)-cinchovatin etc., specifically, uses (-)-cinchovatin.In the presence of (-)-cinchovatin, file asymmetric michael addition/aldolisation, be by 'beta '-ketoester as acceptor, the quinine Alkaloid can be induced asymmetric michael addition reaction effectively, obtains (5) more reposefully.Mixture (5) with diastereomer is converted into (6) then.(6) be at MsCl 5 equivalents, triethylamine 10 equivalents and DMAP 1 equivalent, under the room temperature, 2h, in methylene dichloride the reaction and obtain.Then at AcONa 1 equivalent, 120 ℃, 24h reacts in acetate and obtains (7).Part optical activity three ring (+)-and (-)-(7) through recrystallization, the optical purity sample that can obtain at an easy rate expecting (〉=99%ee).Thus again through 4 steps preparation optical purity (-)-selagine.
Description of drawings
Fig. 1. the 'beta '-ketoester synthetic route
Fig. 2. (-)-cinchovatin promotes the pattern of asymmetric michael addition reaction
Fig. 3. (-)-selagine synthetic route
Embodiment
Synthesizing of embodiment 1. intermediate 'beta '-ketoesters
To 1,4-dihydro spiral shell [4,5]-8-decanone 300g (1.9mol) is dissolved in and adds propynoic acid methyl esters 320g (3.8mol) in the solution of the saturated methyl alcohol 6L of ammonia.Reaction mixture is at 100 ℃ of following reflux 10h, and the material internal pressure reaches 200psi to greatest extent.After the cooling, removal of solvent under reduced pressure obtains crude product pyridone (2) 294g, a kind of faint yellow solid.About 250 ℃ of mp.
In room temperature, under the lucifuge, crude product (2) and Ag
2CO
3867g (3.14mol) and methyl iodide 980ml (15.7mol) are dissolved in the solution mixing stirring of chloroform 20L and spend the night.Filter, concentrate, last dynamic axial compression chromatography (DAC) purifying (40% ethyl acetate/hexane) obtains ketal (3) 257g (74%).mp?77.5-78.5℃。
In room temperature, under the nitrogen protection, ketal (3) 116g is dissolved in methylcarbonate 1L, is added drop-wise to the solution that KH 105g (2.62mol) is dissolved in methylcarbonate 4L.Mixture heating up backflow 3h.Add the methyl alcohol termination reaction, remove methyl alcohol under reduced pressure, water residue ethyl acetate extraction, extraction liquid salt water washing, drying is filtered, and concentrates, last dynamic axial compression chromatography (DAC) purifying (20% ethyl acetate/hexane) obtains 'beta '-ketoester (4) 134g (87%), a kind of yellow solid.Mp 71-72 ℃, Rf=0.33 (20% ethyl acetate/hexane).
Synthesizing of embodiment 2. (-)-selagine
At-10 ℃, under the nitrogen protection, in 'beta '-ketoester (4) 25.0mg (0.10mmol) is dissolved in the solution of methylene dichloride 1.0ml and hexane 1.0ml, add Methylacrylaldehyde 88 μ l (1.0mmol) and (-)-cinchovatin 31.0mg (0.10mmol).Mixed solution stirs 253h down at-10 ℃.Behind the concentrating under reduced pressure, dynamic axial compression chromatography on the residue (DAC) purifying (hexane/ethyl acetate, 3/2) obtains (5) 14.6mg (45%), a kind of colorless oil (contain at least 3 kinds of diastereomers, its ratio is 10: 7: 1).
At 0 ℃, under the nitrogen protection, triethylamine 70 μ l (0.50mmol) and DMAP 5.0mg (41 μ mol) and methylsulfonyl chloride 15 μ l (0.19mmol) add (5) 14.6mg (48 μ mol) and are dissolved in the solution of methylene dichloride 1.5ml.Mixed solution at room temperature stirs 2h, pours saturated NH into
4Among the Cl, extract with EtOAc then.The organic layer water and the salt water washing that merge.Concentrating under reduced pressure, dynamic axial compression chromatography on the residue (DAC) purifying (hexane/ethyl acetate, 3/2) obtains (6) 14.1mg (77%), a kind of colorless oil.
(6) 14.1mg (37 μ mol) and NaOAc 4.0mg (49 μ mol) are dissolved in AcOH 1.0ml, and 120 ℃ are heated 24h down.Behind the concentrating under reduced pressure, residue dilutes with saturated sodium bicarbonate, uses ethyl acetate extraction.The organic extract liquid water and the salt water washing that merge.Behind the concentrating under reduced pressure, dynamic axial compression chromatography on the residue (DAC) purifying (hexane/ethyl acetate, 4/1) obtains (+)-7 6.3mg (60%) (64%ee), a kind of colorless oil.This oily matter 6.3mg recrystallization in hexane is obtained optical purity (+)-7 1.33mg for several times, a kind of colourless crystallization (〉=99%ee).mp＝139.5-141.5℃，[α]
20 D+69.9°(c，1.37，CHCl
3)。
At 0 ℃, under the nitrogen protection, in 1.64M n-Butyl Lithium hexane solution 2.9ml (4.5mmol), add the solution that Ethyltriphenylphosphonium brimide 2.0g (5.4mmol) is dissolved in THF 21ml.The gained suspension at room temperature stirs 70min.After being cooled to 0 ℃, slow adding (+)-7 (〉=99%ee) 340mg (1.2mmol) is dissolved in the solution of THF 7.0ml.The gained mixed solution rises to stirring at room 2h.The water termination reaction.After removing THF under reduced pressure, moist residue extracts with EtOAc.The organic extract liquid salt water washing that merges, behind the concentrating under reduced pressure, dynamic axial compression chromatography on the residue (DAC) purifying (hexane/ethyl acetate, 10/1) obtains (+)-8 and 13 (Z)-isomer 327mg (93%), a kind of colorless oil.(+)-8 obtain the analytical pure product by recrystallization in the hexane, a kind of colourless needle crystal, mp 145-147 ℃, [α]
20 D+ 45.0 ° of (c, 0.83, CHCl
3).
(+)-8 and 13 (Z)-isomer 250mg (0.84mmol) is dissolved in methyl alcohol-THF (2: 1) 3.0ml, adds 20%NaOH 1.0ml.Mixed solution is reflux 36h under nitrogen.After the cooling, mixed solution is transferred pH=5-6 with 1N HCl, removes methyl alcohol and THF under reduced pressure.Moist residue extracts with EtOAc.The extraction liquid salt water washing that merges, behind the concentrating under reduced pressure, dynamic axial compression chromatography on the residue (DAC) purifying (eluent ethyl acetate) obtains (+)-9 153mg (64%), a kind of colourless amorphous solid, [α]
20 D+ 42.8 ° of (c, 1.01, CHCl
3).
(+)-9 145mg (0.51mmol), triethylamine 71 μ l (0.51mmol) and diphenylphosphine acylazide thing 110 μ l (0.51mmol) are dissolved in toluene 2.0ml.Under nitrogen protection, 85 ℃ of heating 3h.After the cooling, reaction mixture concentrating under reduced pressure, residue are dissolved in methyl alcohol 2.0ml, gained vlil 27h.Concentrating under reduced pressure, dynamic axial compression chromatography on the residue (DAC) purifying (methylene dichloride/ether, 20/1) obtains (+)-10 106mg (66%), a kind of colourless caramel sample product, [α]
20 D+ 20.5 ° of (c, 1.20, CHCl
3).
Under room temperature, nitrogen protection, iodate trimethyl silane 453 μ l (3.2mmol) add (+)-10 100mg (0.32mmol) and are dissolved in the solution of chloroform mixed solution reflux 12h.After the cooling, add methyl alcohol 12ml, the gained mixed solution 12h that refluxes again.Concentrating under reduced pressure, residue dilutes with methylene dichloride, use 10% S-WAT, saturated sodium bicarbonate and salt water washing successively, the organic extract liquid concentrating under reduced pressure, dynamic axial compression chromatography on the residue (DAC) purifying (EtOAc/MeOH, 20/3), obtains (-)-1 [(-)-selagine] 62.6mg, a kind of colourless prismatic crystal.mp?228.5-230℃，[α]
25 D-149°(c，1.78，CHCl
3)，IR(KBr)：3430，3380，2930，1655，1615，1555，1460，1310，1120，930，835，660，520cm
-1.
1H?NMR(400MHz，CDCl
3)δ：12.89(1H，brs，NH)，7.90(1H，d，J＝9.4Hz，C
4-H)，6.42(1H，d，J＝9.4Hz，C
3-H)，5.49(1H，q，J＝6.7Hz，C
13-H)，5.41(1H，brd，J＝5.0Hz，C
3-H)，3.64-3.58(1H，m，C
9-H)，2.89(1H，dd，J＝16.9，5.2Hz，C
10-H)，2.73(1H，dd，J＝16.9，1.5Hz，C
10-H)，2.15(1H，d，J＝17.0Hz，C
3-H)，2.11(1H，d，J＝17.0Hz，C
6-H)，1.68(3H，d，J＝6.7Hz，C
14-H)，1.55(3H，s，C
12-H)，1.57-1.25(2H，brs，NH
2). EIMS(m/z)：242(M
+)，227，213，187.HREIMS(m/z：Calcd?for?C
15H
18N
2O(M
+)：242.1419.Found：242.1423。
Claims (5)
1, a kind of chirality natural product selagine [(-)-Huperzine A], i.e. (-)-(5R, 9R, 11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydrochysene-7-methyl-5, the asymmetric synthesis novel method of 9-methylene ring cycloocta-12 (1H)-pyridones is chiral reagent synthesizing optical pure (-)-selagine comprising the synthetic of 'beta '-ketoester with the quinine Alkaloid.
2, according to the process of claim 1 wherein that with 1,4-cyclohexanedione-ethylene ketal is a parent material, react 10h with ammonia methyl alcohol saturated solution and propynoic acid methyl esters down at 100 ℃, a step obtains pyridone, uses methyl iodide and Ag again
2CO
3Handle, obtain ketal.Ketal and KH and methylcarbonate carry out esterification, obtain 'beta '-ketoester.
3, according to the process of claim 1 wherein that the quinine Alkaloid comprises (-)-cinchovatin, quinine, Quinidine etc., preferred (-)-cinchovatin that uses.
4, according to the process of claim 1 wherein that in the presence of (-)-cinchovatin, file asymmetric michael addition, aldolisation are as acceptor by 'beta '-ketoester.
5, according to the process of claim 1 wherein, induce asymmetric reduction reaction by the quinine Alkaloid, then with the mixture of diastereomer in the presence of MsCl, triethylamine and DMAP, in room temperature, 2h, reaction in methylene dichloride and obtain conversion.Then, in the presence of AcONa, 120 ℃ of following reaction 24h, reaction obtains active three rings (+) of part-and (-)-intermediate in acetate, behind recrystallization, obtains the optical homochiral selagine.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603631A (en) * | 2012-01-20 | 2012-07-25 | 中国科学院上海有机化学研究所 | Intermediate for synthetizing (-)-huperzine A, synthetic method and application |
| CN102675204A (en) * | 2012-05-15 | 2012-09-19 | 中国科学院上海有机化学研究所 | Intermediate for synthesizing (I)-huperzine A, synthesis method and usage thereof |
| CN103951618A (en) * | 2014-05-09 | 2014-07-30 | 自贡天健生物科技有限公司 | Huperzine A crystal, and preparation method and application thereof |
| CN104151322A (en) * | 2014-06-11 | 2014-11-19 | 苏州景泓生物技术有限公司 | Synthesis method for preparing huperzine A intermediate |
| WO2015007129A1 (en) | 2013-07-15 | 2015-01-22 | 浙江万邦药业股份有限公司 | Preparation of (-)-huperzine a |
| CN105315209A (en) * | 2014-05-26 | 2016-02-10 | 邯郸温康药物中间体研发有限公司 | Huperzine-A intermediate and preparation method thereof |
| US10287249B2 (en) | 2014-10-03 | 2019-05-14 | Amphastar Pharmaceuticals, Inc. | Methods of resolving racemic mixture to obtain (−)-huperzine A |
| CN114716449A (en) * | 2022-04-12 | 2022-07-08 | 浙江工业大学 | Preparation method of 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline |
-
2008
- 2008-07-02 CN CNA2008101329222A patent/CN101333190A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603631B (en) * | 2012-01-20 | 2016-04-13 | 中国科学院上海有机化学研究所 | A kind of intermediate, preparation method and use of synthesis (-)-selagine |
| CN102603631A (en) * | 2012-01-20 | 2012-07-25 | 中国科学院上海有机化学研究所 | Intermediate for synthetizing (-)-huperzine A, synthetic method and application |
| CN102675204A (en) * | 2012-05-15 | 2012-09-19 | 中国科学院上海有机化学研究所 | Intermediate for synthesizing (I)-huperzine A, synthesis method and usage thereof |
| CN102675204B (en) * | 2012-05-15 | 2015-04-01 | 中国科学院上海有机化学研究所 | Intermediate for synthesizing (I)-huperzine A, synthesis method and usage thereof |
| WO2015007129A1 (en) | 2013-07-15 | 2015-01-22 | 浙江万邦药业股份有限公司 | Preparation of (-)-huperzine a |
| US9586904B2 (en) | 2013-07-15 | 2017-03-07 | Zhejiang Wanbang Pharmaceutical Plc. | Preparation of (−)-huperzine A |
| CN103951618A (en) * | 2014-05-09 | 2014-07-30 | 自贡天健生物科技有限公司 | Huperzine A crystal, and preparation method and application thereof |
| CN105315209B (en) * | 2014-05-26 | 2019-01-08 | 邯郸温康药物中间体研发有限公司 | A kind of huperzine intermediate and preparation method thereof |
| CN105315209A (en) * | 2014-05-26 | 2016-02-10 | 邯郸温康药物中间体研发有限公司 | Huperzine-A intermediate and preparation method thereof |
| CN104151322A (en) * | 2014-06-11 | 2014-11-19 | 苏州景泓生物技术有限公司 | Synthesis method for preparing huperzine A intermediate |
| US10287249B2 (en) | 2014-10-03 | 2019-05-14 | Amphastar Pharmaceuticals, Inc. | Methods of resolving racemic mixture to obtain (−)-huperzine A |
| US10829455B2 (en) | 2014-10-03 | 2020-11-10 | Amphastar Nanjing Pharmaceuticals Inc. | Methods of resolving racemic mixture to obtain (−)-Huperzine A |
| CN114716449A (en) * | 2022-04-12 | 2022-07-08 | 浙江工业大学 | Preparation method of 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline |
| CN114716449B (en) * | 2022-04-12 | 2023-09-29 | 浙江工业大学 | Preparation method of 2-methoxy-6-ethylene glycol ketal-5, 7, 8-trihydroquinoline |
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