CN106432199A - Preparation process of optically pure ondansetron and its derivative salts - Google Patents
Preparation process of optically pure ondansetron and its derivative salts Download PDFInfo
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- CN106432199A CN106432199A CN201610843263.8A CN201610843263A CN106432199A CN 106432199 A CN106432199 A CN 106432199A CN 201610843263 A CN201610843263 A CN 201610843263A CN 106432199 A CN106432199 A CN 106432199A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a preparation process of optically pure ondansetron and its derivative salts, comprising: ultrasonically resolving ondansetron raceme by using a chiral tartrate compound as a resolving agent under ultrasonic condition to obtain its diastereomer salt, crystallizing and purifying the diastereomer salt, extracting by alkalization to obtain optically pure levorotatory ondansetron or dextrotatory ondansetron, and optically pure ondansetron salts are prepared with the optically pure levorotatory ondansetron or dextrotatory ondansetron and related acids. The preparation process of optically pure ondansetron and its derivative salts is simple and feasible and high in speed and efficiency, reagents required herein are cheap, the resolving agent is easy to acquire, nontoxic and easy to recycle, and the preparation process is suitable for industrial preparation.
Description
Technical field
The present invention relates to the preparation technology of a kind of optical voidness ondansetron and its salt derivative, belongs to medical synthesis field.
Technical background
Ondansetron is tetrahydro-carbazolone derivative, and its finished product is often present with hydrochloride dihydrate form, chemical name
It is hydrated for 1,2,3,9- tetrahydrochysene -9- methyl -3- [(2- methyl-1 H-imidazole-1-group) methyl] -4H- carbazole -4- keto hydrochloride two
Thing, molecular formula C18H19N3O·HCl·2H2, there is a chiral carbon atom in molecule, with two kinds of configurations of R, S, be to control at present in O
Treat the main component of cytotoxic chemotherapy and radiotherapy postoperative nausea, the choice drug of vomiting.Ondansetron hydrochloride
Medicine has high selectivity to 3 receptor antagonist of 5-hydroxy tryptamine, the nausea and vomiting that can effectively suppress chemotherapy and radiation to cause, and which is right
Dopamine receptor no antagonism, therefore it is reaction not cause outside vertebral body, does not also change Plasma Prolactin Levels, therefore has oral
Absorb that rapid, dosage is little, the advantages of strong drug action, untoward reaction are little.Since listing, its market share rises increasingly, especially
Its oral novel form in 2010 be approved listing so as to relatively reliable, convenient.
Ondansetron still clinically carries out supplying medicine with racemate form at present, not yet has chiral ondansetron to list.
Clinical practice confirms the spatial configuration close relation of pharmaceutical properties and drug molecule, chiral drug different isomer repeatedly
Metabolic pathway and pharmacological action there is different characteristic, can also there is significant difference in biological activity and drug effect, toxic and side effects.So far
Till, existing related research [J.Sep.Sci., 38,1625 (2015)] shows that two chiral photo-isomerisation of ondansetron are known from experience
Existing different drug effect.Shenyang Pharmaceutical University doctor Duan Mingyu et al. [pharmaceutical analysiss magazine, 26,1187 (2006)] is established with ovum
Mucoid is the method for chiral stationary phase separation ondansetron, and for the Stereoselective Pharmacokinetics research after administration, demonstrate,proves
Understand that the big metabolism in mice process of two enantiomer has stereo selectivity.Two chiral enantiomer of ondansetron and internal blood plasma
The combination rate of albumen there is also difference, and the drug activity of internal R type is significantly greater than almost inactive S type, rat intravenous Ang Dan
After the single enantiomer of department's fine jade, configuration is not converted in vivo, and stablizing for this internal configuration turns to its single enantiomer medicine
Listing study there is provided important evidence.Patil P.A. and Kothekar M.A. [Indian.J.Med.Sci., 60,427
(2006)] compared with S configuration and raceme, there is less cardiac toxicity and safety by studying the R configuration for confirming ondansetron.
These all produce and using the higher requirement of proposition to the chiral of ondansetron medicine from now on.
So far, the chiral method for preparing for ondansetron is separated using chromatography.1993, Kelly
Et al. J.W. [Journal of Chromatography, 622,291 (1993)] is reported for the first time and is used high performance liquid chromatography
Method, i.e., realize separating ondansetron as chiral stationary phase with protein and cellulose derivative.Shenyang Pharmaceutical University of China section
Also application is divided as chiral stationary phase bright doctor Yu et al. [pharmaceutical analysiss magazine, 26,1187 (2006)] with ovomucoid
Method from ondansetron.Then, Shenyang Pharmaceutical University Guo Xing outstanding person et al. [analytical chemistry research noteses, 35,880 (2007)] uses
Amylose Chiral Stationary Phase achieves the chiral separation to ondansetron.2012, Gao Jia et al. [pharmaceutical analysiss magazine, 21,
2951 (2012)] chiral separation of ondansetron hydrochloride enantiomer is realized using high performance capillary electrophoresis.Although chromatography
Occupy some technical advantages with capillary tube method in the microseparation of material and analysis, but as which is relatively costly, expensive,
And easily pollute, therefore this preparation method cannot effectively utilizes to actual industrial metaplasia product.
Ultrasound wave has the effects such as heat effect, mechanical effect, cavitation effect, emulsifying and diffusion, can increase the fortune of molecule
Dynamic speed, strengthen molecule penetration capacity, with simple to operate, reaction condition gentle, the time is short the features such as, at present extensively answer
For aspects such as natural product active ingredient extraction, organic synthesiss.When ultrasound wave is propagated in a liquid, can also cause the super of uniqueness
Sound cavitation effect, produces high temperature, the high pressure of local in liquid internal, and with strong shock wave and microjet.This office
The high-energy environment in portion can cause and acceleration molecular thermal dissociation, molecular ionization and produce free radical etc., so as to possess cause and plus
The energy of fast series of chemical.Compared with chromatography and capillary tube method and traditional chemical resolution method, using ultrasound
Split the highly purified diastereoisomeric salt method of acquisition simple to operate, quickly, efficiently, it is easy to make which be extended to commercial production, and can
While obtaining each enantiomer.At home and abroad have no that ondansetron ultrasound splits the report of preparation method at present in data, but can
Predicting the method for splitting acquisition optical voidness ondansetron using ultrasound can become the chiral improvement of such antiemetic from now on and face
The effectively industrially prepared technology of bed development.
Content of the invention
Present invention aim at providing a kind of optical voidness ondansetron of efficient quick and its salt derivative preparation technology.The work
Ondansetron racemic modification ultrasound effectively can be split into optically pure left-handed ondansetron and dextrorotation ondansetron by skill, and
And multiple optical voidness ondansetron salt derivatives are easily formed in preparation technology.
A kind of optical voidness ondansetron and its preparation technology of salt derivative, using chiral tartaric acids under ultrasound condition
Resolving agent carries out ultrasonic fractionation to ondansetron racemic modification, obtains diastereoisomeric salt, carries out recrystallization to the enantiomer salt pure
Changing, optically pure left-handed ondansetron or dextrorotation ondansetron after alkalization, is extracted, optical voidness is finally prepared into related acid and is held high
Dan Siqiong salt.
A kind of optical voidness ondansetron and its preparation technology of salt derivative, specifically include following steps：
(1) ultrasound splits：
Generation under ultrasonication in resolution solvent is corresponding to chiral tartaric acids resolving agent for racemic modification ondansetron
Diastereoisomeric salt, sucking filtration, be divided into mother solution and filter cake；Or split with chiral tartaric acids first with racemic modification ondansetron
Agent is mixed to get the diastereoisomeric salt of racemization, then will be pure by ultrasonication in resolution solvent to the salt and raceme ondansetron
Change diastereoisomeric salt, sucking filtration, it is divided into mother solution and filter cake；Or ultrasound and heater meanses are utilized by racemic modification ondansetron and handss
Property tartaric acids resolving agent generate corresponding diastereoisomeric salt in 60～100 DEG C of reactions in resolution solvent, then at room temperature from
Separate out in resolution solvent, sucking filtration, be divided into mother solution and filter cake；
(2) recrystallization：
The filter cake that upper step is obtained is placed in recrystallisation solvent and carries out one or many recrystallization, until corresponding diastereomer
Salt optical purity is purified to more than 98%；
(3) alkalization is separated：
The diastereoisomeric salt that step (2) is obtained is alkalized with inorganic base in organic solvent and water, then organic solvent is divided
Concentrate after separating out, be filtrated to get optically pure left-handed ondansetron or the dextrorotation ondansetron of single configuration.
Also include step (4) to reach more preferable effect：To extract after mother liquid obtained for step (1) alkalization, utilize
Compared with chiral tartaric acids resolving agent another kind of configuration tartaric acids resolving agent carry out recrystallization reclaim obtain and dextrorotation Ang Dan
Department's fine jade compares the optical voidness ondansetron of another configuration.
Preparation technology also includes salt-forming steps：By optically pure for gained left-handed ondansetron or dextrorotation ondansetron, and not
Become salt with acid in water or organic solvent, obtain corresponding optical voidness ondansetron salt derivative.
Described chiral tartaric acids resolving agent isWherein R=C1-C20Alkane
Base, alkoxyl, carbonyl, ester group, halogen, nitro or hydrogen, specially O, O '-dibenzoyl tartaric acid, O ,-two pairs of methylbenzene first of O '
Acyl tartaric acid, O, O '-di-p-methoxy benzoyltartaric acid, O ,-two p-nitrophenyl formyl tartaric acid of O ', O, the adjacent chlorobenzene of O '-two
Formyl tartaric acid or O, the O Multi substituted benzenes formyl tartaric acid of '-two.
Chiral tartaric acids resolving agent is 1 with the mol ratio of ondansetron racemic modification:4-1:1.
Described resolution solvent or recrystallisation solvent are selected from water, esters, alcohols, ketone, alkanes, ethers, chloride class, fragrance
One or two and above mixed solvent in class, amide solvent；Wherein esters are formic acid esters, acetass, propionic ester, fourth
Acid esters, aromatic esters；Wherein alcohols is methanol, ethanol, propanol, benzyl alcohol；The ketone is acetone, butanone；Wherein alkanes
For C5-C20Alkane；Wherein ethers is petroleum ether, ether, propyl ether, butyl ether, glycol dimethyl ether, glycol monoethyl ether, tetrahydrochysene furan
Mutter；Wherein chloride class is chloroform, dichloromethane, monochloro methane；Wherein aromatics are benzene,toluene,xylene；Wherein amide-type is
N,N-dimethylformamide.
Step (3) described alkalization be in potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate
Or carry out in the alkaline solution such as potassium bicarbonate, the pH value of alkalization is 7.5～14.
Acid solution described in salt-forming steps is selected from hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, citric acid, mandelic acid, maleic acid, rich horse
Acid and any one or several mixture solutions of tartaric acid.
Optical voidness ondansetron of the present invention and its salt derivative technique, with advantages below：
(1 (and the present invention uses chiral tartaric acids derivatives as resolving agent, ultrasound split ondansetron obtain single
Enantiomer salt, directly or only needs to the enantiomer salt of acquisition high-optical-purity by the 1-2 recrystallization, technique
Simple possible；
(2 (present invention possesses the advantage for splitting that speed is fast, simple to operate, effect is good using supercritical ultrasonics technology, or even certain
Under the conditions of only need a few minutes can obtain efficient ultrasound split effect.
(3 (present invention is not high to producing equipment requirements, and simple to operate, experimental period is short, and the reagent used in experiment is cheap,
Environmental pollution is little, utilization rate height；
(4 (separate the mother solution of the chiral tartaric acid salt derivative of ondansetron enantiomer, can conveniently reclaim mother in the present invention
Ondansetron in liquid, carries out ultrasound using the crystallization of another configuration resolving agent and splits recovery, can obtain another configuration optical voidness and hold high
Dan Siqiong, remaining solution is also recyclable in the technical process.While in whole process, tartaric acids resolving agent can also have
Effect is recycled；
(5 (and the present invention utilize multiple organic and mineral acid, with optical voidness Ang Dan in mixed solution of the water with organic solvent
Department's Qiongjie conjunction, conveniently prepares the optical voidness ondansetron salt derivative of various features, extends the scope of application of the product.
Specific embodiment
Embodiment one：
Weighing 0.147g ondansetron raceme and 0.18g O, O '-dibenzoyl-D-tartaric acid resolving agent is put into 50ml
In round-bottomed flask, add 10ml methanol, ultrasound 30 minutes after, sucking filtration, obtain 0.189g white powdery solids-dextrorotation ondansetron
O, O '-dibenzoyl-D-tartrate, optical purity be 85.7%ee, yield be 57.8%.
Embodiment two：
Weighing 0.147g ondansetron raceme and 0.18g O, O '-dibenzoyl-D-tartaric acid resolving agent is put into 50ml
In round-bottomed flask, 15ml acetone and 3ml water is added, ultrasonic wave added is heated to reflux 1 hour, and solid dissolves quickly, solution is clarified, quiet
Put or stir and cool down three hours, sucking filtration, obtain O, the O of 0.180g white powdery solids-dextrorotation ondansetron '-dibenzoyl-D-
Tartrate, it is 55.0% that optical purity is 88.3%ee, yield.
Embodiment three：
Weigh 0.147g ondansetron raceme and 0.193g O, O '-two couple toluyl-D- tartaric acid resolving agent is put
Enter in 50ml round-bottomed flask, add 25ml butyl acetate, ultrasound 30 minutes after, sucking filtration, obtain 0.184g white powdery solids-right side
O, O '-two couple toluyl-D- tartrate of rotation ondansetron, it is 54.1% that optical purity is 85.7%ee, yield.
Example IV：
Weigh 0.147g ondansetron raceme and 0.193g O, O '-two couple toluyl-D- tartaric acid resolving agent is put
Enter in 50ml round-bottomed flask, 25ml methanol is added, after dissolving, solvent is evaporated, obtains 0.34g white solid.Ang Dansi is separately weighed
Fine jade 0.147g is put in 50mL round-bottomed flask, addition 25mL methanol, ultrasonic dissolution, is added the first step and is obtained 0.34g white admittedly
Body, ultrasound 30 minutes after, sucking filtration, obtain O, O '-two couple methylbenzene first of 0.215g white powdery solids-dextrorotation ondansetron
Acyl-D- tartrate, it is 31.6% that optical purity is 90.9%ee, yield.
Embodiment five：
Weigh 0.147g ondansetron raceme and 0.219g O, O '-di-p-methoxy benzoyl-D- tartaric acid resolving agent
It is put in 50ml round-bottomed flask, 18ml dichloromethane and 5ml methanol is added, ultrasonic wave added is heated to reflux 1 hour, and solid is molten quickly
Solution, solution is clarified, and standing or stirring are cooled down three hours, and sucking filtration obtains the O of 0.160g white powdery solids-dextrorotation ondansetron,
O '-di-p-methoxy benzoyl-D- tartrate, it is 43.7% that optical purity is 91.4%ee, yield.
Embodiment six：
Weigh 0.147g ondansetron raceme and 0.219g O, O '-di-p-methoxy benzoyl-D- tartaric acid resolving agent
It is put in 50ml round-bottomed flask, 10mlTHF and 2ml water is added, ultrasound is after 30 minutes, sucking filtration, obtain 0.153g white powder solid
O, the O of body-dextrorotation ondansetron '-di-p-methoxy benzoyl-D- tartrate, optical purity is that 93.2%ee, yield is
41.8%.
Embodiment seven：
Weigh 0.147g ondansetron raceme and 0.224g O, the O p-nitrophenyl formyl-D- tartaric acid resolving agent of '-two is put
Enter in 50ml round-bottomed flask, 25ml ethanol is added, after dissolving, solvent is evaporated, obtains 0.37g white solid.Ang Dansi is separately weighed
Fine jade 0.147g is put in 50mL round-bottomed flask, addition 25mL ethanol, ultrasonic dissolution, is added the first step and is obtained 0.37g white admittedly
Body, ultrasound 20 minutes after, sucking filtration, obtain O, the O p-nitrophenyl first of '-two of 0.253g white powdery solids-dextrorotation ondansetron
Acyl-D- tartrate, it is 34.1% that optical purity is 93.9%ee, yield.
Embodiment eight：
Weigh 0.147g ondansetron raceme and 0.224g O, the O p-nitrophenyl formyl-D- tartaric acid resolving agent of '-two is put
Enter in 50ml round-bottomed flask, 10mlN, dinethylformamide and 1ml water is added, ultrasonic wave added is heated to reflux 1 hour, and solid is very
Dissolve soon, solution is clarified, standing or stirring are cooled down three hours, sucking filtration obtains 0.184g white powdery solids-dextrorotation ondansetron
O, the O p-nitrophenyl formyl-D- tartrate of '-two, optical purity be 89.8%ee, yield be 49.6%.
Embodiment nine：
Weigh 0.147g ondansetron raceme and 0.214g O, O '-two neighbour's chlorobenzoyl-D- tartaric acid resolving agent is put into
In 50ml round-bottomed flask, 15ml isopropanol is added, ultrasonic wave added is heated to reflux 1 hour, and solid dissolves quickly, solution is clarified, quiet
Put or stir and cool down three hours, sucking filtration, obtain O, O '-two neighbour's chlorobenzene first of 0.175g white powdery solids-dextrorotation ondansetron
Acyl-D- tartrate, it is 48.5% that optical purity is 92.3%ee, yield.
Embodiment ten：
Weigh 0.147g ondansetron raceme and 0.214g O, O '-two neighbour's chlorobenzoyl-D- tartaric acid resolving agent is put into
In 50ml round-bottomed flask, add 30ml glycol dimethyl ether, ultrasound 30 minutes after, sucking filtration, obtain 0.168g white powdery solids-
O, O '-two neighbour's chlorobenzoyl-D- tartrate of dextrorotation ondansetron, it is 46.5% that optical purity is 95.7%ee, yield.
Embodiment 11：
In Example one to ten, the D- tartaric acids salt derivative of the dextrorotation ondansetron of arbitrary 85-96%ee exists respectively
Recrystallization 1-2 time in THF, sucking filtration obtains white solid, and recrystallization yield is 70-90%.Take the solid after recrystallization to be dissolved in
THF, adds in the solution of sodium hydroxide, and it is 7.5～11 to adjust pH, and solution is clarified by muddy change, plus a small amount of water, and revolving is fallen organic molten
Dextrorotation ondansetron is filtered to obtain after agent, and optical purity is 98.5-99.0%ee.Water acid is adjusted to pH=1～2, and resolving agent is analysed
Go out, filter, recycling use, the resolving agent response rate more than 90%.
Embodiment 12：
In difference Example one to ten, the D- tartaric acids salt derivative of the dextrorotation ondansetron of arbitrary 85-96%ee is in first
Recrystallization 1-2 time in alcohol, sucking filtration obtains white solid, and recrystallization yield is 70-90%.Take the solid after recrystallization and be dissolved in first
Alcohol, adds in the solution of sodium carbonate, and it is 7.5～11 to adjust pH, and solution is clarified by muddy change, plus a small amount of water, and revolving falls organic solvent
After filter to obtain dextrorotation ondansetron, optical purity be 98.5-99.0%ee.Water acid is adjusted to pH=1～2, and resolving agent is separated out,
Filter, recycling use, the resolving agent response rate more than 90%.
Embodiment 13：
Filter the mother solution for staying in Example one to ten, solvent evaporated, it is dissolved in methanol, adds the methanol of sodium bicarbonate
Solution, adjusts pH to be more than 7.5, and solution is clarified by muddy change, plus a small amount of water, and revolving is filtrated to get white solid after falling organic solvent.
Water acid is adjusted to pH=1～2, and resolving agent is separated out, and filters, recycling use, the resolving agent response rate more than 90%.
Embodiment 14：
The white solid for obtaining is reclaimed in Example 13 as another configuration ondansetron for reclaiming according to corresponding
The method of embodiment one to ten, with the corresponding L-TARTARIC ACID analog derivative mixing of equal proportion, obtains white solid, according still further to reality
Apply the method recrystallization of example ten one to ten two.Gained white solid is dissolved in methanol, the methanol solution of sodium bicarbonate is added, adjust
PH is more than 7.5, and solution is clarified by muddy change, plus a small amount of water, and revolving is filtrated to get left-handed ondansetron, optics after falling organic solvent
Purity is more than 99.0%ee.Water acid is adjusted to pH=1～2, and resolving agent is separated out, and filters, recycling use, and resolving agent is reclaimed
Rate more than 90%.
Embodiment 15：
Weighing 0.147g ondansetron raceme and 0.18g O, O '-dibenzoyl-L-tartaric acid resolving agent is put into 50ml
In round-bottomed flask, add 10ml methanol, ultrasound 30 minutes after, sucking filtration, obtain 0.175g white powdery solids-left-handed ondansetron
O, O '-dibenzoyl-L-tartaric acid salt, optical purity be 86.2%ee, yield be 53.5%.
Embodiment 16：
Weighing 0.147g ondansetron raceme and 0.18g O, O '-dibenzoyl-L-tartaric acid resolving agent is put into 50ml
In round-bottomed flask, 15ml acetone and 3ml water is added, ultrasonic wave added is heated to reflux 1 hour, and solid dissolves quickly, solution is clarified, quiet
Put or stir and cool down three hours, sucking filtration, obtain O, the O of 0.186g white powdery solids-left-handed ondansetron '-dibenzoyl-L-
Tartrate, it is 56.9% that optical purity is 87.9%ee, yield.
Embodiment 17：
Weigh 0.147g ondansetron raceme and 0.193g O, O '-two couple toluyl-L-TARTARIC ACID resolving agent is put
Enter in 50ml round-bottomed flask, add 25ml butyl acetate, ultrasound 30 minutes after, sucking filtration, obtain 0.193g white powdery solids-left side
O, O '-two couple toluyl-L-TARTARIC ACID salt of rotation ondansetron, it is 56.8% that optical purity is 86.7%ee, yield.
Embodiment 18：
Weigh 0.147g ondansetron raceme and 0.193g O, O '-two couple toluyl-L-TARTARIC ACID resolving agent is put
Enter in 50ml round-bottomed flask, 25ml methanol is added, after dissolving, solvent is evaporated, obtains 0.34g white solid.Ang Dansi is separately weighed
Fine jade 0.147g is put in 50mL round-bottomed flask, addition 25mL methanol, ultrasonic dissolution, is added the first step and is obtained 0.34g white admittedly
Body, ultrasound 30 minutes after, sucking filtration, obtain O, O '-two couple methylbenzene first of 0.223g white powdery solids-left-handed ondansetron
Acyl-L-TARTARIC ACID salt, it is 32.8% that optical purity is 91.7%ee, yield.
Embodiment 19：
Weigh 0.147g ondansetron raceme and 0.219g O, O '-di-p-methoxy benzoyl-L-TARTARIC ACID resolving agent
It is put in 50ml round-bottomed flask, 18ml dichloromethane and 5ml methanol is added, ultrasonic wave added is heated to reflux 1 hour, and solid is molten quickly
Solution, solution is clarified, and standing or stirring are cooled down three hours, and sucking filtration obtains the O of 0.163g white powdery solids-left-handed ondansetron,
O '-di-p-methoxy benzoyl-L-TARTARIC ACID salt, it is 44.5% that optical purity is 90.5%ee, yield.
Embodiment 20：
Weigh 0.147g ondansetron raceme and 0.219g O, O '-di-p-methoxy benzoyl-L-TARTARIC ACID resolving agent
It is put in 50ml round-bottomed flask, 10mlTHF and 2ml water is added, ultrasound is after 30 minutes, sucking filtration, obtain 0.156g white powder solid
O, the O of body-left-handed ondansetron '-di-p-methoxy benzoyl-L-TARTARIC ACID salt, optical purity is that 93.8%ee, yield is
42.6%.
Embodiment 21：
Weigh 0.147g ondansetron raceme and 0.224g O, O '-two p-nitrophenyl formyl-L-TARTARIC ACID resolving agent is put
Enter in 50ml round-bottomed flask, 25ml ethanol is added, after dissolving, solvent is evaporated, obtains 0.37g white solid.Ang Dansi is separately weighed
Fine jade 0.147g is put in 50mL round-bottomed flask, addition 25mL ethanol, ultrasonic dissolution, is added the first step and is obtained 0.37g white admittedly
Body, ultrasound 20 minutes after, sucking filtration, obtain O, the O p-nitrophenyl first of '-two of 0.259g white powdery solids-left-handed ondansetron
Acyl-L-TARTARIC ACID salt, it is 34.9% that optical purity is 94.3%ee, yield.
Embodiment 22：
Weigh 0.147g ondansetron raceme and 0.224g O, O '-two p-nitrophenyl formyl-L-TARTARIC ACID resolving agent is put
Enter in 50ml round-bottomed flask, 10mlN, dinethylformamide and 1ml water is added, ultrasonic wave added is heated to reflux 1 hour, and solid is very
Dissolve soon, solution is clarified, standing or stirring are cooled down three hours, sucking filtration obtains 0.172g white powdery solids-left-handed ondansetron
O, O '-two p-nitrophenyl formyl-L-TARTARIC ACID salt, optical purity be 91.2%ee, yield be 46.4%.
Embodiment 23：
Weigh 0.147g ondansetron raceme and 0.214g O, O '-two neighbour's chlorobenzoyl-L-TARTARIC ACID resolving agent is put into
In 50ml round-bottomed flask, 15ml isopropanol is added, ultrasonic wave added is heated to reflux 1 hour, and solid dissolves quickly, solution is clarified, quiet
Put or stir and cool down three hours, sucking filtration, obtain O, O '-two neighbour's chlorobenzene first of 0.173g white powdery solids-left-handed ondansetron
Acyl-L-TARTARIC ACID salt, it is 47.9% that optical purity is 92.7%ee, yield.
Embodiment 24：
Weigh 0.147g ondansetron raceme and 0.214g O, O '-two neighbour's chlorobenzoyl-L-TARTARIC ACID resolving agent is put into
In 50ml round-bottomed flask, add 30ml glycol dimethyl ether, ultrasound 30 minutes after, sucking filtration, obtain 0.171g white powdery solids-
O, O '-two neighbour's chlorobenzoyl-L-TARTARIC ACID salt of left-handed ondansetron, it is 47.4% that optical purity is 94.5%ee, yield.
Embodiment 25：
Respectively in Example ten five to two 14, the L-TARTARIC ACID class of the left-handed ondansetron of arbitrary 85-96%ee derives
Salt recrystallization 1-2 time in THF, sucking filtration obtains white solid, and recrystallization yield is 70-90%.Take the solid after recrystallization molten
In THF, add in the solution of sodium hydroxide, it is 7.5～11 to adjust pH, and solution is clarified by muddy change, plus a small amount of water, and revolving is fallen organic
Left-handed ondansetron is filtered to obtain after solvent, and optical purity is 98.5-99.0%ee.Water acid is adjusted to pH=1～2, resolving agent
Separate out, filter, recycling use, the resolving agent response rate more than 90%.
Embodiment 26：
Respectively in Example ten five to two 14, the L-TARTARIC ACID class of the left-handed ondansetron of arbitrary 85-96%ee derives
Salt recrystallization 1-2 time in methyl alcohol, sucking filtration obtains white solid, and recrystallization yield is 70-90%.Take the solid after recrystallization molten
In methanol, add in the solution of sodium carbonate, it is 7.5～11 to adjust pH, and solution is clarified by muddy change, plus a small amount of water, and revolving is fallen organic
Left-handed ondansetron is filtered to obtain after solvent, and optical purity is 98.5-99.0%ee.Water acid is adjusted to pH=1～2, resolving agent
Separate out, filter, recycling use, the resolving agent response rate more than 90%.
Embodiment 27：
Filter the mother solution for staying in Example ten five to two 14, solvent evaporated, it is dissolved in methanol, adds sodium bicarbonate
Methanol solution, adjust pH to be more than 7.5, solution is clarified by muddy change, plus a small amount of water, and revolving is filtrated to get white after falling organic solvent
Solid.Water acid is adjusted to pH=1～2, and resolving agent is separated out, and filters, recycling use, the resolving agent response rate more than 90%.
Embodiment 28：
The white solid for obtaining is reclaimed in Example 27 as another configuration ondansetron for reclaiming according to relative
The method for answering embodiment ten five to two 14, with the corresponding D- tartaric acids derivatives mixing of equal proportion, obtains white solid,
Method recrystallization according still further to embodiment 20 five to two 16.Gained white solid is dissolved in methanol, adds sodium bicarbonate
Methanol solution, adjust pH to be more than 7.5, solution is clarified by muddy change, plus a small amount of water, is filtrated to get dextrorotation and holds high after revolving organic solvent
Dan Siqiong, optical purity is more than 99.0%ee.Water acid is adjusted to pH=1～2, and resolving agent is separated out, and filters, and reclaiming circulation makes
With the resolving agent response rate more than 90%.
Embodiment 29：
0.2 gram of optical voidness dextrorotation ondansetron in Example 11,12 and 28, add 50ml concentration be
The ethanol solution hydrochloride of 0.02mol/L, under ice-water bath after stirring half an hour, is spin-dried for solvent, and drying under reduced pressure obtains optical voidness dextrorotation
0.22 gram of ondansetron hydrochloride solid.
Embodiment 30：
In Example 11,12 and 28,0.2 gram of optical voidness dextrorotation ondansetron, is dissolved in methanol, stirring
Deca 1ml acetic acid, under ice-water bath after stirring half an hour, is spin-dried for solvent, and drying under reduced pressure obtains optical voidness dextrorotation ondansetron acetic acid
0.24 gram of salt solid.
Embodiment 31：
In Example 11,12 and 28,0.2 gram of optical voidness dextrorotation ondansetron, is dissolved in THF, stirring drop
Plus 0.1 gram of tartaric acid, under ice-water bath after stirring half an hour, solvent is spin-dried for, optical voidness dextrorotation Ang Dansi is obtained with a small amount of water filtration
0.3 gram of fine jade tartrate solid.
Embodiment 32：
0.2 gram of the left-handed ondansetron of optical voidness in Example 14,25 and 26, add 50ml concentration be
The ethanol solution hydrochloride of 0.02mol/L, under ice-water bath after stirring half an hour, is spin-dried for solvent, and it is left-handed that drying under reduced pressure obtains optical voidness
0.22 gram of ondansetron hydrochloride solid.
Embodiment 33：
In Example 14,25 and 26,0.2 gram of the left-handed ondansetron of optical voidness, is dissolved in ether, stirs
Deca 1ml acetic acid is mixed, under ice-water bath after stirring half an hour, solvent is spin-dried for, drying under reduced pressure obtains the left-handed ondansetron vinegar of optical voidness
0.24 gram of hydrochlorate solid.Embodiment 34：
In Example 14,25 and 26,0.2 gram of the left-handed ondansetron of optical voidness, is dissolved into ethyl acetate
In, 0.1 gram of tartaric acid of agitation and dropping, under ice-water bath after stirring half an hour, solvent being spin-dried for, an optical voidness left side is obtained with a small amount of water filtration
0.3 gram of rotation ondansetron tartrate solid.
Claims (9)
1. the preparation technology of a kind of optical voidness ondansetron and its salt derivative, it is characterised in that：Using chiral tartaric acids
Compound is chiral resolving agent, coordinates ul-trasonic irradiation, carries out chiral separation to raceme ondansetron, obtain diastereoisomeric salt,
Recrystallization purifying is carried out to the diastereoisomeric salt, and optically pure left-handed ondansetron or dextrorotation Ang Dansi is extracted after alkalization
Fine jade, is finally prepared into optical voidness ondansetron salt with related acid.
2. a kind of preparation technology of optical voidness ondansetron, it is characterised in that：Specifically include following steps：
(1) ultrasound splits：
Racemic modification ondansetron and chiral tartaric acids resolving agent generate corresponding non-in resolution solvent under ultrasonication
Enantiomer salt, sucking filtration, it is divided into mother solution and filter cake；Or it is mixed with chiral tartaric acids resolving agent first with racemic modification ondansetron
The diastereoisomeric salt for obtaining racemization is closed, then will be non-by ultrasonication purification in resolution solvent to the salt and raceme ondansetron
Enantiomer salt, sucking filtration, it is divided into mother solution and filter cake；Or ultrasound and heater meanses are utilized by racemic modification ondansetron and chiral wine
Stone acids resolving agent generates corresponding diastereoisomeric salt in 60～100 DEG C of reactions in resolution solvent, then at room temperature from fractionation
Separate out in solvent, sucking filtration, be divided into mother solution and filter cake；
(2) recrystallization：
The filter cake that upper step is obtained is placed in recrystallisation solvent and carries out one or many recrystallization, until corresponding diastereoisomeric salt light
Learn purity and be purified to more than 98%；
(3) alkalization is separated：
The diastereoisomeric salt that step (2) is obtained is alkalized with inorganic base in organic solvent and water, then organic solvent is isolated
After concentrate, be filtrated to get optically pure left-handed ondansetron or the dextrorotation ondansetron of single configuration.
3. a kind of preparation technology of optical voidness ondansetron as claimed in claim 2, it is characterised in that：Also include step (4)：
To extract after mother liquid obtained for step (1) alkalization, using another kind of configuration tartaric acid compared with chiral tartaric acids resolving agent
Class resolving agent carries out recrystallization and reclaims the optical voidness ondansetron for obtaining another configuration compared with dextrorotation ondansetron.
4. a kind of preparation technology of optical voidness ondansetron as claimed in claim 2 or claim 3, it is characterised in that：Preparation technology is also
Including salt-forming steps：By optically pure for gained left-handed ondansetron or dextrorotation ondansetron, from different acid in water or organic solvent
In become salt, obtain corresponding optical voidness ondansetron salt derivative.
5. a kind of preparation technology of optical voidness ondansetron as claimed in claim 2 or claim 3, it is characterised in that：Described chirality
Tartaric acids resolving agent is
Wherein R=C1-C20Alkyl, alkoxyl, carbonyl, ester group, halogen, nitro or
Hydrogen；Specially O, O '-dibenzoyl tartaric acid, O, O '-two couples of toluyl tartaric acid, O, O '-di-p-methoxy benzoyl
Tartaric acid, O ,-two p-nitrophenyl formyl tartaric acid of O ', O, the adjacent chlorobenzoyl tartaric acid of O '-two or O, the O Multi substituted benzenes first of '-two
Acyl tartaric acid.
6. a kind of preparation technology of optical voidness ondansetron as claimed in claim 2, it is characterised in that：Chiral tartaric acids are torn open
It is 1 with the mol ratio of ondansetron racemic modification to divide agent:4-1:1.
7. a kind of preparation technology of optical voidness ondansetron as claimed in claim 2, it is characterised in that：Described resolution solvent
Or the one kind of recrystallisation solvent in water, esters, alcohols, ketone, alkanes, ethers, chloride class, aromatics, amide solvent
Or two kinds and above mixed solvent；Wherein esters are formic acid esters, acetass, propionic ester, butyrate, aromatic esters；Wherein alcohol
Class is methanol, ethanol, propanol, benzyl alcohol；The ketone is acetone, butanone；Wherein alkanes are C5-C20Alkane；Wherein ethers
For petroleum ether, ether, propyl ether, butyl ether, glycol dimethyl ether, glycol monoethyl ether, tetrahydrofuran；Wherein chloride class be chloroform,
Dichloromethane, monochloro methane；Wherein aromatics are benzene,toluene,xylene；Wherein amide-type is N,N-dimethylformamide.
8. a kind of preparation technology of optical voidness ondansetron as claimed in claim 2, it is characterised in that：Step (3) alkali
Change be in the alkaline solution such as potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate
Carry out, the pH value of alkalization is 7.5～14.
9. a kind of preparation technology of optical voidness ondansetron as claimed in claim 4, it is characterised in that：Described in salt-forming steps
Acid solution selected from hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, citric acid, mandelic acid, maleic acid, fumaric acid and tartaric acid any one or several
Mixture solution.
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