CN109336897A - A kind of galanthamine hydrobromide industrialized process for preparing - Google Patents
A kind of galanthamine hydrobromide industrialized process for preparing Download PDFInfo
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- CN109336897A CN109336897A CN201811484186.7A CN201811484186A CN109336897A CN 109336897 A CN109336897 A CN 109336897A CN 201811484186 A CN201811484186 A CN 201811484186A CN 109336897 A CN109336897 A CN 109336897A
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- weiding
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- galanthamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to technical field of medicine synthesis, and in particular to a kind of preparation method of galanthamine hydrobromide.For preparation method of the invention the following steps are included: that dimension of raceme is set to raw material by (1), addition resolution solvent obtains left-handed Na Weiding；(2) left-handed Na Weiding is restored into obtain galanthamine free alkali through 3-sec-butyl lithium borohydride, galanthamine hydrobromide is further reacted to obtain with hydrobromic acid.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to a kind of preparation method of galanthamine hydrobromide.
Background technique
Galanthamine is one specific with selectivity, competitiveness and reversible acetylcholinesterase inhibitor.Separately
Effect of the internal acetylcholine to nicotinergic receptor also can be improved outside, mechanism, which may is that, carries out nicotinic transmission
Allosteric is adjusted, and the above mechanism of action enhances the activity of Alzheimer type old dementia patients cholinergic system, while improving trouble
The cognitive function of person.
Galanthamine ratified in July, 2000 by European Union as Kang Aercihaimoshi disease (AD) drug after for the first time in English
State, Ireland listing.Galanthamine hydrobromide piece was ratified to list on 2 28th, 2001 by FDA, trade name
RAZADYNE is mainly used for treating slight or moderate Alzheimer's disease in the U.S..In China, galanthamine is oral often to be released
Dosage form and injection have been included in national medical insurance directory Class B.This product has been proposed as the drug of first choice for the treatment of AD in many countries at present
Object has extensive market application prospect.
Existing preparation method:
1) US 2006/0009640A1 and US6369238B1 first prepares racemic modification galanthamine, then right with D- (+)-
Methyldiphenyl formyl tartaric acid ((+) para-toluoyltartaric acid monohydrate) carries out chiral inversion, yield
Low, chiral reagent is at high cost, is not suitable for large-scale production.
2) Organic Process Reserch&Development, 1999,3,425 synthesize (-)-by (-)-Na Weiding
When galanthamine, using the Stereoselective reduction agent country L-Selectride, L-Selectride without manufacturer, need into
Mouthful, it is expensive and be difficult to obtain.
3) Yan Jiaqi: CN1554658A and Liu Tao etc.: journal of Zhejiang university, 2006,40:520 prepare racemic modification Garland
He is quick, and racemic modification galanthamine is not natural products, non-selectivity choline enzyme inhibition, and synthesis obtain also simultaneously
Non- is a kind of product of racemic modification galanthamine, and there are also a kind of galanthamine products to exist, and the two separation is extremely difficult.
It 4) is starting material with 6- bromine an unusually sweet smell aldehyde and tyrasamine in CN200810020491, the two elder generation condensating reductive, then first
Na Weiding derivative is made in acylated, oxidation, cyclization, obtains racemization Na Weiding, a small amount of (-)-Na Wei of racemization Na Weiding through reduction
Surely chiral induction is carried out, is generated (-)-
Na Weiding, then beta-unsaturated ketone is restored with chiral reagent (-)-N- methyl ephedrine, it can be obtained with higher ee value
Optically active alcohol, to be readily available (-)-galanthamine.
Existing preparation method has problems in that:
1) synthetic method that US 2006/0009640A1 and US6369238B1 is provided, low yield, chiral reagent is at high cost,
Be not suitable for large-scale production.
2) Organic Process Reserch&Development, 1999,3,425 synthesize (-)-by (-)-Na Weiding
When galanthamine, using the Stereoselective reduction agent country L-Selectride, L-Selectride without manufacturer, need into
Mouthful, it is expensive and be difficult to obtain.
3) Yan Jiaqi: CN1554658A and Liu Tao etc.: journal of Zhejiang university, 2006,40:520 prepare racemic modification Garland
He is quick, separates extremely difficult.
4) synthetic method provided in CN200810020491, route is long, complicated for operation, and yield is low.
Mainly improved place is the present invention: the present invention provides a kind of preparation method of galanthamine hydrobromide, synthesis
Route is short, easy to operate, and raw material is easy to get.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of galanthamine hydrobromide.
Preparation method of the present invention, comprising the following steps:
(1) with raceme, that dimension is set to raw material, and resolution solvent is added and obtains left-handed Na Weiding；
(2) left-handed Na Weiding is restored into obtain galanthamine free alkali through 3-sec-butyl lithium borohydride, further with hydrobromic acid
React to obtain galanthamine hydrobromide.
Wherein, resolution solvent is the mixed liquor of ethyl alcohol and triethylamine, and the volume ratio of ethyl alcohol and triethylamine is 5-10:1；It splits
The dosage of solvent is 5-10 times of raceme Na Weiding mass.
Wherein, resolution reaction temperature is 30-50 DEG C.
Wherein, the dosage of 3-sec-butyl lithium borohydride, is 0.5-1.0 times of levo form Na Weiding mass, and reaction temperature is
15-25℃。
Preferably, preparation method of the invention, comprising the following steps:
(1) left-handed Na Weiding:
Ethyl alcohol-triethylamine mixed liquor that volume ratio is 5-10:1 is added in reaction flask, Na Weiding is then added, is heated to
Reflux, adds left-handed Na Weiding, cools down, stirs to get suspension, suspension is concentrated, be filtered under diminished pressure, and washed with ice ethyl alcohol
It washs, it is dry, obtain left-handed Na Weiding；
(2) synthesis of galanthamine hydrobromide:
Under protection of argon gas, 1M 3-sec-butyl lithium borohydride-tetrahydrofuran and anhydrous tetrahydro furan are added into reaction flask
Mixed solution, left-handed Na Weiding is added portionwise, stirs, ethyl alcohol is added dropwise, filters, all obtained solution are merged, second is added
Alcohol starts that hydrobromic acid solution is added dropwise, left-handed galanthamine hydrobromide crystal seed is added, filters, and ethanol washing after draining, is filtered
Filtration cakes torrefaction is obtained galanthamine hydrobromide by cake.
Further preferably, preparation method of the invention, comprising the following steps:
(1) left-handed Na Weiding:
Ethyl alcohol-triethylamine mixed liquor 1200ml that volume ratio is 9:1 is added in reaction flask, that dimension of 100g is then added
It is fixed, it is heated to flowing back, then system is cooled to 65-68 DEG C, and the left-handed Na Weiding of 1g is added, and is cooled to 40 DEG C, stirs 3 hours, hangs
Turbid is concentrated into the one third of original volume at 40 DEG C or so, and concentrate system is cooled to 5-10 DEG C, is filtered under diminished pressure, and uses 0-5
DEG C ice ethanol washing, 60 DEG C are dried under reduced pressure, and obtain that left-handed dimension and determine 80.3g；
(2) synthesis of galanthamine hydrobromide:
Under protection of argon gas, it is anhydrous that 1M 3-sec-butyl lithium borohydride-tetrahydrofuran 345ml and 75ml is added into reaction flask
The mixed solution of tetrahydrofuran is cooled to -20 DEG C, is kept for -15 DEG C or so, the left-handed Na Weiding of 80g is added portionwise, system is -15
Insulated and stirred 30min at DEG C, then system is warming up to 20 DEG C, and stirring obtains amber solution for 1 hour, and 29ml ethyl alcohol, control is added dropwise
30 DEG C of temperature keeps 30min, filters, and filter cake is washed with 95ml tetrahydrofuran, and all obtained solution are merged, 95ml second is added
Alcohol cools to 0 DEG C, starts that hydrobromic acid solution is added dropwise, temperature control is at 20 DEG C hereinafter, left-handed galantamine hydrobromide is added less than 1 in adjusting pH
His quick crystal seed, 0-5 DEG C of heat preservation are crystallized 1 hour, are filtered, and ethanol washing after draining, obtains filter cake, 60 DEG C of filter cake are dried to obtain
Galanthamine hydrobromide 101.3g.
The present invention for existing preparation method, have which the utility model has the advantages that
The present invention overcomes present in prior art, at high cost, and raw material is difficult to obtain, and long yield of synthetic route is low equal scarce
It falls into, a kind of method effectively preparing galanthamine hydrobromide is provided, method raw material provided by the invention is easy to get, and step is short, instead
Answer mild condition.
Detailed description of the invention
Fig. 1 is the HNMR map of galanthamine hydrobromide
Fig. 2 is the CNMR map of galanthamine hydrobromide
Fig. 3 is the high resolution mass spectrum figure of galanthamine hydrobromide
Specific embodiment
Below with reference to specific example is implemented, the present invention is further illustrated, it should be appreciated that these embodiments are merely to illustrate this hair
It is bright rather than limit the scope of the invention.
The raw material or reagent used in embodiment are commercially available in addition to special instruction.
The preparation of the left-handed Na Weiding of 1 compound of embodiment
The ethyl alcohol being added in reaction flask-triethylamine mixed liquor (9:1), Na Weiding are heated to flowing back, and then system is cooled to
65-68 DEG C, the left-handed Na Weiding of 1g is added, is cooled to 40 DEG C, stirs 3 hours.Suspension is concentrated into original volume at 40 DEG C or so
One third, concentrate system are cooled to 5-10 DEG C, are filtered under diminished pressure, and with 0-5 DEG C of ice ethanol washing.60 DEG C are dried under reduced pressure,
Obtain product.
The synthesis of 2 galanthamine hydrobromide of embodiment preparation
1M 3-sec-butyl lithium borohydride-tetrahydrofuran, anhydrous tetrahydro furan, mixing is added under argon gas protection into reaction flask
Object is cooled to -20 DEG C, is kept for -15 DEG C or so, is added portionwise left-handed Na Weiding (about 2h), system insulated and stirred at -15 DEG C
30min.Then system is warming up to 20 DEG C, and stirring obtains amber solution for 1 hour, and ethyl alcohol is added dropwise, 30 DEG C of temperature control, keeps 30min.
It filters, filter cake is washed with tetrahydrofuran, and all obtained solution are merged, ethyl alcohol is added, cools to 0 DEG C, starts that hydrogen bromine is added dropwise
At 20 DEG C hereinafter, adjust pH less than 1, left-handed galanthamine hydrobromide crystal seed is added, it is small that 0-5 DEG C of heat preservation crystallizes 1 in acid solution, temperature control
When, it filters, ethanol washing after draining, obtains filter cake, is dried to obtain galanthamine hydrobromide for 60 DEG C of filter cake.
Claims (7)
1. a kind of preparation method of galanthamine hydrobromide, comprising the following steps:
(1) by raceme, that dimension is set to raw material, and resolution solvent is added and obtains left-handed Na Weiding；
(2) left-handed Na Weiding is restored into obtain galanthamine free alkali through 3-sec-butyl lithium borohydride, is further reacted with hydrobromic acid
Obtain galanthamine hydrobromide.
2. preparation method according to claim 1, which is characterized in that resolution solvent is the mixed liquor of ethyl alcohol and triethylamine.
3. preparation method according to claim 1, which is characterized in that the dosage of resolution solvent is raceme Na Weiding mass
5-10 times.
4. preparation method according to claim 1, which is characterized in that ethyl alcohol in resolution solvent: triethylamine=5-10:1.
5. preparation method according to claim 1, which is characterized in that (1) resolution reaction temperature is 30-50 DEG C.
6. preparation method according to claim 1, which is characterized in that (2) dosage of 3-sec-butyl lithium borohydride is left-handed
0.5-1.0 times of body Na Weiding mass, reaction temperature are 15-25 DEG C.
7. preparation method according to claim 1, which comprises the following steps:
(1) left-handed Na Weiding:
Ethyl alcohol-triethylamine mixed liquor 1200ml that volume ratio is 9:1 is added in reaction flask, Na Weiding is then added, is heated to
Reflux, then system is cooled to 65-68 DEG C, adds the left-handed Na Weiding of 1g, is cooled to 40 DEG C, stirs 3 hours, suspension is 40
DEG C or so be concentrated into the one third of original volume, concentrate system is cooled to 5-10 DEG C, is filtered under diminished pressure, and with 0-5 DEG C of ice second
Alcohol washing, 60 DEG C are dried under reduced pressure, and obtain left-handed Na Weiding；
(2) synthesis of galanthamine hydrobromide:
Under protection of argon gas, the mixed of 1M 3-sec-butyl lithium borohydride-tetrahydrofuran and anhydrous tetrahydro furan is added into reaction flask
Solution is closed, is cooled to -20 DEG C, is kept for -15 DEG C or so, left-handed Na Weiding is added portionwise, the insulated and stirred 30min at -15 DEG C, so
System is warming up to 20 DEG C afterwards, and stirring obtains amber solution for 1 hour, and ethyl alcohol is added dropwise, 30 DEG C of temperature control, keeps 30min, filters, filter
Cake is washed with tetrahydrofuran, and all obtained solution are merged, ethyl alcohol is added, cools to 0 DEG C, starts that hydrobromic acid solution is added dropwise,
At 20 DEG C hereinafter, adjust pH less than 1, left-handed galanthamine hydrobromide crystal seed is added, 0-5 DEG C of heat preservation crystallizes 1 hour, pumping in temperature control
Filter, ethanol washing after draining, obtain filter cake, are dried to obtain galanthamine hydrobromide for 60 DEG C of filter cake.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1170395A (en) * | 1994-10-21 | 1998-01-14 | 瓦尔德海姆药物股份有限公司 | Production of derivatives of 4a, 5, 9, 10, 11, 12, -bexahydro-6H-benzofuro [3a, 3, 2, -ef] [2] benzazepine |
| US6369238B1 (en) * | 1994-10-21 | 2002-04-09 | Sanochemia Pharmazeutica | Processes for the preparation of derivatives of 4a, 5, 9, 10, 11, 12-hexahydro-6H-benzofuro-[3a, 3, 2-ef][2]benzazepine |
| WO2007010412A2 (en) * | 2005-05-03 | 2007-01-25 | Medichem, S.A | Syntheses and preparations of narwedine and related novel compounds |
| CN102311367A (en) * | 2011-06-21 | 2012-01-11 | 上海多丹精细化工有限公司 | Benzylamine derivative and application thereof in galanthamine synthesis |
| 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 |
-
2018
- 2018-12-06 CN CN201811484186.7A patent/CN109336897A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1170395A (en) * | 1994-10-21 | 1998-01-14 | 瓦尔德海姆药物股份有限公司 | Production of derivatives of 4a, 5, 9, 10, 11, 12, -bexahydro-6H-benzofuro [3a, 3, 2, -ef] [2] benzazepine |
| US6369238B1 (en) * | 1994-10-21 | 2002-04-09 | Sanochemia Pharmazeutica | Processes for the preparation of derivatives of 4a, 5, 9, 10, 11, 12-hexahydro-6H-benzofuro-[3a, 3, 2-ef][2]benzazepine |
| WO2007010412A2 (en) * | 2005-05-03 | 2007-01-25 | Medichem, S.A | Syntheses and preparations of narwedine and related novel compounds |
| CN102311367A (en) * | 2011-06-21 | 2012-01-11 | 上海多丹精细化工有限公司 | Benzylamine derivative and application thereof in galanthamine synthesis |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| BERNHARD KUENBURG,ET AL.: "Development of a Pilot Scale Process for the Anti-Alzheimer Drug (-)-Galanthamine Using Large-Scale Phenolic Oxidative Coupling and Crystallisation-Induced Chiral Conversion", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| LASZLO CZOLLNER，ET AL.: "New Kilogram-Synthesis of the Anti-Alzheimer Drug (-)-Galanthamine", 《TETRAHEDRON LETTERS》 * |
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Application publication date: 20190215 |