CN101239983A - Chiral synthesis method for (-)-galantamin hydrobromide - Google Patents
Chiral synthesis method for (-)-galantamin hydrobromide Download PDFInfo
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- CN101239983A CN101239983A CNA2008100204910A CN200810020491A CN101239983A CN 101239983 A CN101239983 A CN 101239983A CN A2008100204910 A CNA2008100204910 A CN A2008100204910A CN 200810020491 A CN200810020491 A CN 200810020491A CN 101239983 A CN101239983 A CN 101239983A
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- galanthamine hydrobromide
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Abstract
Ethamine compound is obtained by condensing starting materials of 6-bromoisovanillin and tyramine under catalysis of NaBH<SUB>4</SUB> in carbinol. In formylation of ethamine compound, aminic acid and formaldehyde of same amount are used to produce formyl compound, with temperature between 90 DEG C. and 110 DEG C., 8h. Racemic bromonarwedine is obtain by oxidation and cyclization of the formyl compound. Racemic narwedine is obtained by reduction reaction under catalysis of NaCO<SUB>2</SUB>H, PPh<SUB>3</SUB>, Pd(OAc)<SUB>2</SUB>. Racemic narwedine is transformed into (-)-narwedine by a process of crystal inoculation. (-)-narwedine is reduced into unsaturated ketone by (-)-N-methyl ephedrine as chiral reagent, whereby optically active alcohol is obtained, and (-)-galanthamine is also obtained.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to (-)-the chirality synthetic novel method of galanthamine hydrobromide.
Background technology
Lycoremine (galanthamine) is to extract a kind of left-handed chipal compounds that obtains from the pale reddish brown short-tube lycoris of amrallid (Lycoris squamigera Maxim) and chrysanthemum short-tube lycoris (Lycoris aurea Herb) or kindred plant, it is a kind of high selectivity anticholinesterase, easily tolerance, no liver toxicity.Former clinically poliomyelitis sequela and the myasthenia gravis of being used for now is used for the treatment of Alzheimer, and the dysmnesia that dementia patients and brain organic pathology are caused also have the improvement effect.(-) of Ying Yonging-lycoremine is made hydrobromate usually clinically.
Alzheimer is the elderly's a kind of gradual neural function degenerative imbalance, and clinical manifestation is based on memory loss and cognition dysfunction.Alzheimer is the main form of senile dementia, accounts for the 50-70% of senile dementia.It is one of main dementia of harm humans health, affects thousands of gerontal patients and kinsfolk's life, has also increased heavy burden to society simultaneously, has caused the extensive concern of international community in recent years.Galanthamine hydrobromide has high degree of specificity to the neurone acetylcholinesterase, be one effectively, the newtype drug of low toxicity, become the choice drug of treatment senile dementia at present.Galanthamine hydrobromide is in zone that the height choline lacks as postsynaptic zone active maximum, and the postsynaptic zone is the main mediation district of treatment effect.Galanthamine hydrobromide does not have liver toxicity, better tolerance, and not with protein bound, so the less influence that may be taken food or take medicine simultaneously.
After lycoremine was ratified by European Union in July, 2000, at first after Britain, Ireland listing, in succession in China and 25 also clinical applications of country's listing in the world.
The method of traditional mode of production lycoremine is a separation and Extraction from wild short-tube lycoris, and the content of lycoremine is very little in the short-tube lycoris, and productive rate has only 0.006%, promptly needs about 18～20 tons of short-tube lycoris can extract 1 kilogram of lycoremine.It mainly is that 1. the raw material short-tube lycoris must be wild that extraction lycoremine production cost occupies high reason, gathers difficulty, and transportation, cold are shone, processing treatment is too loaded down with trivial details, and labour intensity is big.2. extract and consume a large amount of solvents in the purge process, have greater environmental impacts, strengthened the environmental improvement cost, 3. be subjected to the restriction of natural plant resource.
Produce lycoremine with chemical synthesis process, replacing plant extraction process with it, to solve the lycoremine source not enough, and the problem that the medicine high price is expensive is scientist's a popular research topic both at home and abroad in recent years.
About the manufacturing of lycoremine, the existent method report is as follows:
1) the body lycoremine is revolved in US 2006/0009640A1 and US 6369238B1 preparation export trade earlier, use D-(+)-methyldiphenyl formyl tartrate ((+)-para-toluoyltartaric acid monohydrate) is carried out chirality transform then, productive rate is lower, the chiral reagent cost is too high, is not suitable for scale operation.
2) Organic Process Reserch﹠amp; Development, 1999,3,425 during by synthetic (-)-lycoremine of (-)-Na Weiding, uses Stereoselective reduction agent L-Selectride, and the domestic no manufacturer of L-Selectride needs import, costs an arm and a leg and is difficult to obtain.
3) Yan Jiaqi: CN1554658A and Liu Tao etc.: journal of Zhejiang university, 2006,40:520 prepares the racemic modification lycoremine, the racemic modification lycoremine is not to be natural product, the non-selectivity choline esterase inhibition, and synthetic what obtain is not to be a kind of product of racemic modification lycoremine yet, also has a kind of racemic modification epigalanthamine to exist, and both separation are difficulty very.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, the manufacture method of (-)-galanthamine hydrobromide of the more favourable suitability for industrialized production of research and design.
The invention provides the new improvement synthetic method of a kind of (-)-galanthamine hydrobromide; it is starting raw material that this method is selected 6-bromine isovanillin and tyrasamine for use; both first condensating reductives; formylation then, oxidation, cyclization make the Na Weiding derivative; obtain racemization Na Weiding through reduction; racemization Na Weiding carries out chiral induction with a small amount of (-)-Na Weiding; generate (-)-Na Weiding; use chiral reagent (-)-N-methyl ephedrine reduction beta-unsaturated ketone again; can obtain optically active alcohol with higher ee value, thereby obtain (-)-lycoremine at an easy rate.
Concrete steps comprise:
(1) starting raw material 6-bromine isovanillin and tyrasamine are 1: 0.5 to 1: 2.0.In methyl alcohol, use NaBH
4Catalyzing and condensing obtains ethylamine compounds.
(2) in the formylation reaction of ethylamine compounds, adopt equivalent formic acid and formaldehyde, 90 ℃-110 ℃ of temperature, 8h.Obtain carbamoyl compound.
(3) oxidation of carbamoyl compound, ring-closure reaction adopt K
2CO
3And the Tripotassium iron hexacyanide, temperature of reaction is 50 ℃-100 ℃.
(4) solvent of reduction reaction is DMF, racemize bromine Na Weiding: NaCO
2H: PPh
3: Pd (OAc)
2It is 1: 1.5: 0.1: 0.05 mol ratio, mixture heating up to 80 ℃-100 ℃, 4-10h.
(5) transform the method that (-)-Na Weiding adopts inoculation crystal (-)-Na Weiding by racemization Na Weiding, the mol ratio between racemization Na Weiding and the inoculum is 10: 0.05 to 10: 0.2.
(6) (-)-Na Weiding obtains optically active alcohol with chiral reagent (-)-N-methyl ephedrine reduction beta-unsaturated ketone, obtains (-)-lycoremine.(-)-Na Weiding is 1: 3.5 to 1: 5.0 with the mol ratio of (-)-N-methyl ephedrine reduction reaction.
Reaction formula is as follows:
Embodiment:
Embodiment
N-(2-bromo-5 hydroxyls-4-methoxybenzyl)-4-hydroxyphenethylamine (2)
Be dissolved in the solution of methyl alcohol 300ml to 6-bromine isovanillin 65g (0.28mol), at room temperature drip (methyl alcohol) solution of tyrasamine 38g (0.28mol).
Mixture stirs 5h.
Be cooled to 0 ℃, gradation adds NaBH on a small quantity
4(0.34mol) 13.4g (minimum for good) to foam.
Reaction solution at room temperature stirs 5h then.(following the tracks of TLC:EtOAc/MSO, 1/3)
Remove methyl alcohol under reduced pressure, the oily residue is dissolved in ethyl acetate, use the salt water washing, pass through anhydrous magnesium sulfate drying.
Be decompressed to driedly, obtain yellow oil 2 82.3g (83.1%) (as HCl salt, mp 229-230 ℃)
N-(2-bromo-5 hydroxyls-4-methoxybenzyl)-4-leptodactyline methylamine (3)
250g (0.14mol) is dissolved in the mixed solution of 98%～100% formic acid 50ml and 36%～38% formaldehyde 50ml.Heat 100 ℃ of stirring and refluxing 8h.
After reaction finished, mixed solution was cooled to room temperature, added 17%HCl 60ml, stirred 20min.
Remove volatilizable solvent under reduced pressure, add entry 150ml, use 10%NH
4OH alkalization, ethyl acetate extraction (3 * 500ml), (combining extraction liquid), by anhydrous magnesium sulfate drying, be decompressed to dried, brown yellow oil product 3 47.3g (91%) that obtain (mp 176-177 ℃). (3 acceptable salts hydrochlorate methods are refining)
Racemize bromine Na Weiding (4)
Toluene 2.67L and the water 333ml 5L interlayer reactor of packing into, mixed solution is heated to 70 ℃ under nitrogen, add K
2CO
333g (0.24mol) and Tripotassium iron hexacyanide 107.8g open homogenizer then, and disposable adding 3 20g (52.6mmol) behind the 30min, close homogenizer, and mixed solution filters to remove a large amount of brown solids.Branch is two-layer, and with 2M NaOH 500ml washing, product is extracted among the 2M HCl 500ml toluene mutually, and extraction liquid adds t-butyl methyl ether 500ml and EtOAc 250ml, and water transfers to neutrality.Organic phase is by dried over sodium sulfate, and concentrating under reduced pressure obtains 4 6.27g (33%).
Racemize Na Weiding (5)
DMF (N, dinethylformamide) 930ml adds 4187.3g (515mmol), NaCO
2H 52.5g (772mmol), PPh
313.5g (51mmol), Pd (OAc)
25.78g (26mmol) with NaCl 3.76g (103mmol).Mixture heating up to 94 ℃, 6h.The GC demonstration reacts completely.The mixture of black filters with methylene dichloride 2L dilution, adds 2MNaOH 2L, layering.Product extracts from methylene dichloride with 2M HCl 2L.Join again among the methylene dichloride 2L, transfer pH=12 with 46～48%NaOH.Tell dichloromethane layer, be concentrated into about 200ml.Add MeOH100ml, the methylene dichloride evaporation with remnants forms solid product, filters and collects, and with the cold methanol washing, obtains product 5122.2g (84%) .purity 〉=95%by HPLC.
(-)-Na Weiding (6)
54g (14mmol) is dissolved in ethanol 80ml, 85 ℃ of solution heating, 1h.Make 5 dissolvings fully.Then, add (-)-Na Weiding crystal seed 0.5g (1.4mmol), mix liquid and cool the temperature to 40 ℃, under this temperature, continue to stir 12h.Cool the temperature to 20 ℃ again, filter, collect crystallization, obtain 63.72g (93%) (99.1%ee).([α]
20 D＝-400°，c＝1.5in?CHCl
3)。
(-)-galanthamine hydrobromide (1)
6 (〉=98%ee), 117g adds lithium aluminum hydride (～M diethyl ether solution) 1404ml under 0 ℃, and (-)-N-methyl ephedrine 269g and N-ethyl-2-aminopyridine 362.7g is dissolved in the mixture of ether, and the gained mixture stirs 4h under this temperature.Add 1M NaOH solution 11.7L, the product dichloromethane extraction, the organic layer evaporation obtains (-)-lycoremine (98%ee) (85%).(-)-lycoremine is placed methyl alcohol, slowly add 47% liquid hydrogen bromic acid methanol solution, continue down to stir 2h, be cooled to 0～5 ℃, continue to stir 90min, the solid methanol wash that leaches at 25～30 ℃.Solids obtains 1134.1g (99%), the colourless crystallization product in 55 ~ 60 ℃ of drying under reduced pressure 4 ~ 6h.([α]
D=-92 °, c=1.5in H
2O, literature value-93 °, c=1 in H
2O)
1N?NMR(DMSO-d
6)δ10.50(bs，1H)，6.85(AB，2H，J＝9.6Hz)，6.15(d，1H，J＝7.9Hz)，5.95(dd，1H，J＝7.9Hz，J＝3.2Hz)，4.85(d，1H，J＝16.0Hz)，4.60(s，1H)，4.47(bs，1H)，4.35(d，1H，J＝16.0Hz)，4.10(bs，1H)，3.70-3.90(s+m，4H)，3.50(d，1H，J＝12.8Hz)，2.85(bs，3H)，2.40-2.20(m，3H)，1.90(d，1H，J＝16.0Hz)；
13C?NMR(DMSO-d
6)(clearly?distinguishablesignals；b＝very?broad?and?small?signals)δ146.3，144.8，132.8，129.8，125.4，122.9，121.2(b)，111.9，86.3，59.4，57.5(b)，55.6，53.7(b)，46.4，30.9.
Claims (7)
1, the synthetic method of a kind of (-)-galanthamine hydrobromide; it is characterized in that this method is: with 6-bromine isovanillin and tyrasamine is starting raw material; both first condensating reductives; formylation then, oxidative coupling make the Na Weiding derivative; obtain racemization Na Weiding through reduction; racemization Na Weiding carries out chiral induction with a small amount of (-)-Na Weiding; generate (-)-Na Weiding; use chiral reagent (-)-N-methyl ephedrine reduction beta-unsaturated ketone again, can obtain optical activity (-)-lycoremine with higher ee value.
2, the synthetic method of a kind of (-) according to claim 1-galanthamine hydrobromide is characterized in that starting raw material 6-bromine isovanillin and tyrasamine are 1: 0.5 to 1: 2.0.
3, the synthetic method of a kind of (-) according to claim 1-galanthamine hydrobromide is characterized in that in the formylation reaction of wherein said step 2, adopts equivalent formic acid and formaldehyde, 90 ℃-110 ℃ of temperature, 8h.
4, the synthetic method of a kind of (-) according to claim 1-galanthamine hydrobromide is characterized in that the oxidation of wherein said step 3, ring-closure reaction adopt K
2CO
3And the Tripotassium iron hexacyanide, temperature of reaction is 50 ℃-100 ℃.
5, the synthetic method of a kind of (-) according to claim 1-galanthamine hydrobromide is characterized in that wherein said step 4, and the solvent of reduction reaction is DMF, racemize bromine Na Weiding: NaCO
2H: PPh
3: Pd (OAc)
2It is 1: 1.5: 0.1: 0.05 mol ratio, mixture heating up to 80 ℃-100 ℃, 4-10h.
6, the synthetic method of a kind of (-) according to claim 1-galanthamine hydrobromide, it is characterized in that wherein said step 5, transform the method that (-)-Na Weiding adopts inoculation crystal (-)-Na Weiding by racemization Na Weiding, the mol ratio between racemization Na Weiding and the inoculum is 10: 0.05 to 10: 0.2.
7, the synthetic method of a kind of (-) according to claim 1-galanthamine hydrobromide, it is characterized in that wherein said step 6, (-)-Na Weiding obtains optically active alcohol with chiral reagent (-)-N-methyl ephedrine reduction beta-unsaturated ketone, obtains (-)-lycoremine.(-)-Na Weiding is 1: 3.5 to 1: 5.0 with the mol ratio of (-)-N-methyl ephedrine.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101781305A (en) * | 2010-03-23 | 2010-07-21 | 泰州市今朝伟业精细化工有限公司 | Method for artificially synthesizing galanthamine |
| CN103421014A (en) * | 2012-05-16 | 2013-12-04 | 天津市海格力科技发展有限公司 | Synthesis method of galanthamine |
| CN104592243A (en) * | 2014-12-19 | 2015-05-06 | 北京大学 | Asymmetric synthesis method of galanthamine and lycoramine |
| CN106977412A (en) * | 2017-05-15 | 2017-07-25 | 张家港威胜生物医药有限公司 | A kind of preparation method of galanthamine key intermediate |
| WO2023221022A1 (en) * | 2022-05-19 | 2023-11-23 | 暨南大学 | Method for preparing galanthamine, derivative thereof and intermediate thereof |
-
2008
- 2008-03-10 CN CNA2008100204910A patent/CN101239983A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101781305A (en) * | 2010-03-23 | 2010-07-21 | 泰州市今朝伟业精细化工有限公司 | Method for artificially synthesizing galanthamine |
| CN103421014A (en) * | 2012-05-16 | 2013-12-04 | 天津市海格力科技发展有限公司 | Synthesis method of galanthamine |
| CN103421014B (en) * | 2012-05-16 | 2014-07-09 | 天津市海格力科技发展有限公司 | Synthesis method of galanthamine |
| CN104592243A (en) * | 2014-12-19 | 2015-05-06 | 北京大学 | Asymmetric synthesis method of galanthamine and lycoramine |
| CN106977412A (en) * | 2017-05-15 | 2017-07-25 | 张家港威胜生物医药有限公司 | A kind of preparation method of galanthamine key intermediate |
| CN106977412B (en) * | 2017-05-15 | 2019-08-02 | 张家港威胜生物医药有限公司 | A kind of preparation method of galanthamine key intermediate |
| WO2023221022A1 (en) * | 2022-05-19 | 2023-11-23 | 暨南大学 | Method for preparing galanthamine, derivative thereof and intermediate thereof |
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Open date: 20080813 |