CN106938986A - A kind of preparation method of antiepileptic eslicarbazepine acetate - Google Patents
A kind of preparation method of antiepileptic eslicarbazepine acetate Download PDFInfo
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- CN106938986A CN106938986A CN201610003282.XA CN201610003282A CN106938986A CN 106938986 A CN106938986 A CN 106938986A CN 201610003282 A CN201610003282 A CN 201610003282A CN 106938986 A CN106938986 A CN 106938986A
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- licarbazepine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
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Abstract
The invention provides a kind of preparation method of antiepileptic eslicarbazepine acetate.This method is using Oxcarbazepine as initiation material; racemic acetic acid licarbazepine is obtained after reduction and acetylization reaction, lipase hydrolysis is then continued through and light prolongs reaction and the enantiomter of eslicarbazepine acetate in racemic mixture is completely converted into eslicarbazepine acetate.
Description
Technical field
The present invention relates to the synthetic method of eslicarbazepine acetate, belong to pharmaceutical synthesis field.
Background technology
Eslicarbazepine acetate (Eslicarbazepineacetate) is for raising carbamazepine (Carbamazepine) and Austria
The curative effect and tolerance of oxcarbazepine (Oxcarbazepine) and a kind of Newer antiepileptic developed, were listed in 2009.And Austria
Oxcarbazepine is the same, and it is also the prodrug of eslicarbazepine, mainly realized by blocking voltage gated sodium channels it is anticonvulsion and
The therapeutic action of two-way stable mood.Compared with former generation medicine, eslicarbazepine acetate have safe, compliance it is good,
The low advantage of side effect, can not only significantly reduce the seizure frequency of difficulty to control epilepsy partial seizures patient, can also reduce
The generation of depressive symptom is so as to improve the quality of life of patient.
In existing literature and patent, the common methods of synthesis eslicarbazepine acetate have following several：
Patent CN200680036421.3 and CN200710112634.6 use the method that asymmetric chemistry is synthesized, with O'Casey
Put down as initiation material, obtain obtaining acetic acid Ai Sili after eslicarbazepine, acetylation using asymmetric catalytic hydrogenation reduction reaction
Oxcarbazepine.Reactions steps are brief, but the catalyst that asymmetric hydrogenation is used is rare precious metals ruthenium Ru and organic ligand shape
Into complex, both prices are sufficiently expensive, and recovery process is complicated, is not appropriate for the production of scale.
Patent CN02813993.3 and CN200480019893.9 is disclosed using Oxcarbazepine as initiation material, in second alcohol and water
Racemic licarbazepine is obtained in mixed solution with sodium borohydride reduction, is then existed in pyridine and DMAP
Under the conditions of with resolution reagent (2R, 3R)-two-O, O '-acetyl group winestone anhydride reaction, be recrystallizing repeatedly so as to obtain diastereoisomer
The sour half ester of 10-O- bis--O, O '-acetyltartaric, is finally obtaining eslicarbazepine acetate after hydrolysis, acetylation.The method
Belong to chemical resolution method, target isomer is enriched with by recrystallizing repeatedly using the difference in diastereoisomer physicochemical property.
Complex steps in practical operation, time-consuming, yield it is relatively low be this method major defect.
Patent WO2006056339 with 5- cyano group -10- hydroxyls -10,11- dihydro -5H- dibenzo [b, f] azatropylidene be initiation material,
(S) -5- cyano group -10- hydroxyl -10,11- dihydro -5H- dibenzo is obtained with being split after phthalic anhydride by (S) -1- phenyl ethylamines
[b, f] azatropylidene, is finally obtaining eslicarbazepine acetate after hydrolysis, acetylation.The method also belongs to chemical resolution method,
Limitation in actual applications is equally obvious.
Recently as continuing to develop for biotechnology, the method that chipal compounds are prepared using biocatalytic reaction is more and more.
Patent CN102465159 is using the saccharomyces cerevisiae CGCCNo.2230 somatic cells containing enzyme for acquisition of fermenting as catalyst carrier, profit
Eslicarbazepine is obtained with internal cell coenzyme I (NADH) reduction Oxcarbazepines, then obtains after acetylation acetic acid Chinese mugwort department
Licarbazepine, reactions steps are shorter.But viable bacteria catalysis requires that accurate, strain variation causes reaction there is also reaction condition simultaneously
Efficiency and selectivity decline, the shortcomings of fermentation costs are higher.
Patent WO2011045648 discloses a kind of using the licarbazepine for hydrolyzing enzyme resolution of racemic, then passes through number step chemistry
React the method for obtaining eslicarbazepine acetate.This method needs just obtain product by the reaction of 5 steps, and process is relatively complicated.
The half isomers opposite with product configuration can not change into product in addition, therefore the overall yield of technique is relatively low, large-scale production
It is less efficient.
Patent CN100582095C, which is disclosed, a kind of to be prolonged reaction (Mitsunobu reaction) using light and prepares optically pure acetic acid
The method of eslicarbazepine.This method is prolonged the chiral center of reaction using optically pure (S)-licarbazepine as raw material, by light and entered
Row upset, finally obtains the eslicarbazepine acetate of correct configuration.From the angle of large-scale production, (S)-licarbazepine
It is difficult to obtain as eslicarbazepine acetate, and the method disclosed in the patent fails to solve (S)-licarbazepine to carry out source problem.
The content of the invention
It is an object of the invention to provide a kind of method for preparing antiepileptic eslicarbazepine acetate, advantage be production cost it is low,
Reactions steps are simple, high income, be adapted to large-scale production.
The preparation method of the present invention is different from chemical resolution method and microorganism catalysis method, and what is utilized is enzymatic Split Method.Bacterium,
Generally there is stereoselectivity during the fatty acid ester of the microbe-derived Lipase catalyzed hydrolysis chiral alcohol formation such as fungi, i.e., can only
The fatty acid ester of one of configuration chiral alcohol formation is hydrolyzed, and its isomers can not be hydrolyzed.The method of the present invention utilizes lipase
(R)-isomers in the acetic acid licarbazepine of hydrolysis of racemic, has obtained (R)-licarbazepine, while in racemic mixture
Some eslicarbazepine acetates are unaffected.
The lipase wanted needed for the preparation method of the present invention can be obtained easily by commercial sources.Lipase food processing,
The fields such as process hides, sewage disposal are all widely used, less-restrictive of originating.Catalytic activity of lipase is universal higher, ensure with
On the premise of substrate is fully contacted, less usage amount can be completed in a relatively short time reaction.
The present invention preparation method another substantial improvement is that：Obtained (R)-sharp cassie need not be reacted to lipase-catalyzed
Gentle eslicarbazepine acetate mixture is separated, and directly prolongs reaction (Mitsunobu reaction) by mixture using light
In (R)-licarbazepine be converted into eslicarbazepine acetate, and original eslicarbazepine acetate is unaffected in mixture.
In actual production, the innovation has two significances：
(1) such that licarbazepines all in theory can change into end-product eslicarbazepine acetate, so as to breach existing
Have to split in method and can only obtain the limitation of 50% theoretical yield.
(2) in actual production, after the lipase-catalyzed greatest problem that runs into when being split applied to chiral material is typically catalysis
The separation of chiral product.It is close in view of (R)-licarbazepine and eslicarbazepine acetate physicochemical property, can not readily it lead to
Cross the modes such as recrystallization, vacuum fractionation to remove, the method for chromatogram post separation is not suitable for large-scale production again.The preparation side of the present invention
Method avoids separating step so that the technique split using lipase is in the practical of large-scale production time-varying.
In summary, " lipase hydrolysis+light the prolongs reaction " route used in preparation method of the invention, and avoid to fat
The mix products that fat enzymatic is obtained carry out complicated lock out operation.Reaction is prolonged to (R)-licarbazepine progress configuration reversal by light
Acetylization reaction realize efficient, the inexpensive utilization to opposite configuration intermediate, be whole syntheti c route reaction yield
Improve by about one time.This is also that the preparation method of the present invention is better than the important feature of existing method.
What the present invention was realized particular by following technical scheme：
Preparing reaction equation is：
Reduction reaction：
Using Oxcarbazepine as initiation material, racemic licarbazepine is obtained with reducing agent reaction.Dried licarbazepine is (outer
Racemization) it is dissolved in jointly in solvent with acid binding agent, 0-4 DEG C is cooled to, acetylizing agent is slowly added to.It is warming up to after completion of dropping
25 DEG C, and continue stirring question response terminate after, obtain acetic acid licarbazepine (racemic).Wherein reducing agent may be selected sodium borohydride,
The reducing substanceses such as Sodium triacetoxyborohydride, three acetonitrile-base sodium borohydrides, borine；Acid binding agent may be selected pyridine, triethylamine,
The alkaline matters such as potassium carbonate；Chloroacetic chloride, acetic anhydride may be selected in acetylizing agent；Acylation reaction solvent may be selected dichloromethane, chloroform,
The non-protonic solvents such as tetrahydrofuran.
Enzyme catalyzed hydrolysis：
Acetic acid licarbazepine (racemic) is dissolved in organic solvent, lipase freeze-dried powder is soluble in water.The consumption of lipase is
The 0.05%-0.2% of acetic acid licarbazepine (racemic) quality.Acetic acid licarbazepine (racemic) solution is added under stirring
In fatty enzyme aqueous solution, it is that near 30 DEG C, it is 7-8 to add appropriate bases and keep reacting liquid pH value to keep reacting liquid temperature.One
Enzymatic reaction terminates after fixing time, and it is about 1 to obtain mol ratio：1 (R)-licarbazepine and the mixing of eslicarbazepine acetate
Thing.Wherein dichloromethane, chloroform etc. may be selected in organic solvent；Sodium acid carbonate, sodium carbonate, potassium carbonate etc. may be selected in alkali.
Light prolongs reaction (Mitsunobu reaction)：
The mixture of dried (R)-licarbazepine and the mixture of eslicarbazepine acetate is dissolved in appropriate solvent, added
Appropriate triphenylphosphine and acetic acid, is cooled to 0-4 DEG C, is slowly added to diisopropyl azodiformate.After question response is complete,
Obtain final product eslicarbazepine acetate.Wherein reaction dissolvent is dichloromethane, chloroform, tetrahydrofuran etc.；Triphenyl
Phosphine can use tributylphosphine to substitute；Diisopropyl azodiformate can use diethyl azodiformate to substitute.
Case is embodied
Following embodiments further illustrates the present invention, but is not construed as limiting the present invention in any way.
Embodiment 1
Add to stir under Oxcarbazepine (2.52kg, 10mol) and ethanol (25L), normal temperature into 200L reactors and be allowed to
Fully dissolved.Sodium borohydride (0.378kg, 10mol) is divided into 5 batches, every batch to be spaced 30 minutes, added under agitation
State in solution.Charging continues to stir at normal temperatures 2 hours after finishing.Question response adds water (50L) after terminating, stirring is used in combination
After reaction solution pH is adjusted to 7 by concentrated hydrochloric acid, the solid of precipitation is filtered and collected.Then 50L is concentrated the filtrate to refilter
Once and collect solid.Two batches solid is dried after merging, and obtains licarbazepine (racemic) solid 2.42kg.
Dried licarbazepine (racemic) solid (2.42kg, 9mol) is dissolved in anhydrous two in 200L reactors
In chloromethanes (50L), anhydrous pyridine (2.3L, 28.5mol) is added.Solution is cooled down to 0 DEG C, is slowly added under stirring
Anhydrous methylene chloride (10L) solution of chloroacetic chloride (0.81L, 11.4mol), and keep reacting liquid temperature to be no more than 4 DEG C.
After after two hours or so completion of dropping, 25 degree are warming up to, continues to stir 3 hours.Reaction terminates to add water (50 in backward reaction solution
L 4-5) and with NaOH by reacting liquid pH value is adjusted to, is stood after stirring half an hour.Dichloro is collected after being layered completely
Methane layer, evaporated under reduced pressure and oxcarbazepine acetic acid esters (racemic) the solid 2.65kg that gets profit after drying.
Lipase used by case study on implementation of the present invention is purchased from Mike woods Reagent Company (No. CAS：9001-62-1).In 200L reactions
Lipase freeze-dried powder (3g) and sodium acid carbonate (756g, 9mol) are dissolved in water (90L) in kettle, lower add of stirring will
Solution of licarbazepine acetic acid esters (racemic) solid (2.65kg, 8.93mol) in dichloromethane (10L), and protect
Reacting liquid temperature is held for 30 DEG C.After stirring 12 hours, dichloromethane (50L) is added, continues to filter after stirring 30 minutes.
By filtrate stratification, dichloromethane layer is collected.Decompression steaming vibrating dichloromethane after obtain eslicarbazepine acetate (i.e. (S)-
Licarbazepine acetic acid esters) and the hybrid solid of (R)-licarbazepine (mol ratio is about 1：1).
About 10g drying solids are taken, are ended using (the R)-licarbazepine and acetic acid that purity more than 99% is respectively obtained after chromatogram post separation
Licarbazepine is taken charge of, specific rotatory power is determined：(R) D25=-194.9 ° of-licarbazepine [α] (c=1, pyridine), acetic acid Ai Sili cassies
Flat D25=21.6 ° of [α] (c=1, pyridine).
The mixture of above-mentioned eslicarbazepine acetate and (R)-licarbazepine is dissolved in anhydrous methylene chloride in 200L reactors
In (50L), triphenylphosphine (1.42kg, 5.4mol), glacial acetic acid (0.31L, 5.4mol) are added.Reaction solution is cold
But arrive be slowly added under 0-4 DEG C, stirring diisopropyl azodiformate (1.06L) anhydrous methylene chloride (10L) it is molten
Liquid, and keep reacting liquid temperature to be no more than 10 DEG C.Completion of dropping after one hour, is warming up to 25 DEG C and continues to stir 12 hours.
After question response terminates, the difficult saturated aqueous solution (30L) of bicarbonate, stratification after stirring are added into reaction solution.Collect two
By dichloromethane evaporated under reduced pressure and drying after chloromethanes layer, eslicarbazepine acetate (99%) is obtained after recrystallization, 2.15kg,
Total recovery since initiation material is 73%, [α]D 25=21.6 ° (c=1, pyridine), HPLC measures purity 99%, mapping
Body excess ee ＞ 99%.
Embodiment 2
Raw material is 500g Oxcarbazepines, is reacted with 75g sodium borohydrides, and product obtains 470g licarbazepines after drying (outer
Racemization).470g licarbazepines (racemic) and 0.45L anhydrous pyridines are dissolved in 7L anhydrous tetrahydro furans, slowly
0.2L acetic anhydrides are added dropwise.Esterification obtains acetic acid licarbazepine (racemic) 508g after terminating.0.25g lipase is frozen
Reaction is hydrolyzed under being stirred with 500g acetic acid licarbazepine (racemic) in the two phase liquid of water and chloroform in dry powder, keeps
Reaction temperature is 30 DEG C, keeps reaction solution pH in 7-8.Reaction obtains (R)-licarbazepine and acetic acid Ai Sili cassies after terminating
Flat mixture, anhydrous tetrahydro furan is dissolved in after drying, and adds 280g triphenylphosphines and 61mL acetic acid, stirring it is lower slow plus
Enter diethyl azodiformate 0.2L.After reaction terminates, end-product eslicarbazepine acetate 405g, [α] are obtainedD 25=21.6 °
(c=1, pyridine), the total recovery since initiation material measures purity 99%, enantiomeric excess ee ＞ 99% for 70%, HPLC.
Embodiment 3
Raw material is 5kg Oxcarbazepines, is reacted with 0.756kg sodium borohydrides, and product obtains 4.4kg licarbazepines after drying (outer
Racemization)；4.4kg licarbazepines (racemic) and 3L triethylamines are dissolved in 40L anhydrous methylene chlorides, are slowly added dropwise
2L acetic anhydrides.Esterification obtains acetic acid licarbazepine (racemic) 4.6kg after terminating；By 10g lipase freeze-dried powder with
Reaction is hydrolyzed in 4.6kg acetic acid licarbazepine (racemic) under being stirred in the two phase liquid of water and dichloromethane, keep anti-
It is 30 DEG C to answer temperature, keeps reaction solution pH in 7-8.Reaction obtains (R)-licarbazepine and eslicarbazepine acetate after terminating
Mixture, be dissolved in anhydrous methylene chloride after drying, add 3kg triphenylphosphines and 0.6L acetic acid, idol is slowly added under stirring
Nitrogen dioctyl phthalate diisopropyl ester 0.2L.After reaction terminates, end-product eslicarbazepine acetate 4.3kg, [α] are obtainedD 25=21.6 °
(c=1, pyridine), the total recovery since initiation material measures purity 99%, enantiomeric excess ee ＞ 99% for 74%, HPLC.
Claims (5)
1. a kind of preparation method of eslicarbazepine acetate, it is characterized in that：
Preparing reaction equation is：
(1) using Oxcarbazepine as raw material, racemic licarbazepine is obtained by reducing agent reduction；
(2) racemic acetic acid licarbazepine is obtained by racemic licarbazepine and the reaction of suitable acetylizing agent；
(3) by (R)-isomers in lipase selective hydrolysis racemic acetic acid licarbazepine, (R)-licarbazepine and vinegar are obtained
The mixture of sour eslicarbazepine；
(4) using acetic acid as reactant, using light prolong reaction by (R) in the mixture of (R)-licarbazepine and eslicarbazepine acetate-
Licarbazepine is converted into eslicarbazepine acetate.
2. the preparation method of a kind of eslicarbazepine acetate according to claim 1, it is characterized in that reducing agent is sodium borohydride.
3. a kind of preparation method of eslicarbazepine acetate according to claim 1, it is characterized in that acetylizing agent be chloroacetic chloride,
Acetic anhydride.
4. the preparation method of a kind of eslicarbazepine acetate according to claim 1, it is characterized in that the consumption of lipase is vinegar
The 0.05%~0.2% of sour licarbazepine quality.
5. the preparation method of a kind of eslicarbazepine acetate according to claim 1, it is characterized in that the light prolongs reaction three
Replace progress in the presence of phosphine and azo agents, wherein the three substitutions phosphine is triphenylphosphine or tributylphosphine, the azo agents are
Diisopropyl azodiformate or diethyl azodiformate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108840825A (en) * | 2018-07-24 | 2018-11-20 | 天津安浩生物科技有限公司 | The recrystallization purifying technique of the precursor reactant of catalytic asymmetric hydrogenation |
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- 2016-01-04 CN CN201610003282.XA patent/CN106938986A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108840825A (en) * | 2018-07-24 | 2018-11-20 | 天津安浩生物科技有限公司 | The recrystallization purifying technique of the precursor reactant of catalytic asymmetric hydrogenation |
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