CN104177271B - A kind of preparation method of ALC - Google Patents
A kind of preparation method of ALC Download PDFInfo
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- CN104177271B CN104177271B CN201410282991.7A CN201410282991A CN104177271B CN 104177271 B CN104177271 B CN 104177271B CN 201410282991 A CN201410282991 A CN 201410282991A CN 104177271 B CN104177271 B CN 104177271B
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Abstract
The present invention relates to field of medicine preparations, specifically disclose the preparation method of a kind of ALC.Levocarnitine and glacial acetic acid are mixed by the present invention, drip excess acetyl chloride, add the first solvent crystallization after completion of the reaction under low temperature, filter, and precipitate dried ALC crude product；Then in crude product, add the second solvent, heating, drip the 3rd solvent, filter after solid dissolves, filtrate slowly reduces temperature to room temperature, then low temperature crystallize, filters, and precipitates dried ALC fine work.The present invention uses multiple suitable organic solvent to use according to certain sequential combination, ALC is separated and refines, the content of reduction impurity A and unreacted raw material levocarnitine is all below 0.05%, and the ALC fine work purity of preparation reaches more than 99.90%.
Description
Technical field
The present invention relates to field of medicine preparations, be specifically related to the preparation method of a kind of ALC.
Background technology
Levocarnitine, chemistry entitled (R)-3-carboxyl-2-hydroxy-n, in N, N-trimethyl the third ammonium hydroxide
Salt, is internal natural materials required in mammalian energy metabolism.Levocarnitine be muscle cell especially
Being the main energy sources of myocardial cell, many histoorgans such as brain, kidney also supply mainly by fatty acid oxidation
Energy.For various tissue ischemia anoxias, levocarnitine improves histoorgan by increasing energy generation
Energy supply.Other functions of levocarnitine have: the Oxidation of medium long-chain fatty acid；Fatty acid peroxidase
The Oxidation of thing enzyme；To the coenzyme A combined and the cushioning effect of free both coenzyme As ratio；From ketone
Class material, acetone acid, aminoacid (including branched-chain amino acid) produce energy, removes too high coenzyme A
Toxicity, regulation blood in ammonia density.
The chemical constitution of levocarnitine is shown below:
ALC (Acetyl Levocarnitine Hydrochloride, ALC), chemistry is entitled
(R)-4-(N, N, N-trimethylamino)-3-acetoxyl group butyrate hydrochlorate, for the derivant of levocarnitine.Salt
Acid acetyl levocarnitine be trimethylamino acid esters, it via acetyl levocarnitine transferring enzyme human body brain,
It is synthesized at liver.It can promote the mitochondrion picked-up to S-acetyl-coenzyme-A during fatty acid oxidation,
Increase the generation of acetylcholine, and stimulating protein and the synthesis of membrane phospholipid.Acetyl-L-carnitine hydrochloride energy
Enough run through blood brain barrier, improve neural energy, repair effects on neural system mechanism and regulate central nervous system
The generation of acetylcholine in system.
ALC is developed by Sigma-Taug company of Italy the earliest, and indication is
Treatment alzheimer disease, the most continuously in country's listings such as Argentina, Korea S, indication has A Erzi sea
Silent disease, depression, disturbance of cerebral circulation, cardiovascular disorder, diabetes with secondary damages, cognitive disorder
Alcoholic liver disease etc..
The structure of ALC is shown below:
Document reports the preparation method of multiple ALC, and general method is with Zuo Kani
Spit of fland is raw material, prepares with excess acetyl chloride in certain solvent, and synthetic method is as follows:
Such as, " Helvetica Cheimica Acta " 1987 volume 70 page 2063 reports acetyl chloride
The synthetic method of levocarnitine: levocarnitine and chloroacetic chloride reacting by heating in glacial acetic acid, is evaporated off surplus
Glacial acetic acid and chloroacetic chloride, obtain ALC crude product, and crude product prepares with recrystallisation from isopropanol and closes
Lattice product.The weak point of this synthetic method is: (1) glacial acetic acid consumption is big；(2) due to chlorination
Acetyl levocarnitine dissolubility in acetic acid is relatively big, and low temperature also is difficult to crystallize, post processing elder generation recovered under reduced pressure mistake
The chloroacetic chloride of amount and solvent glacial acetic acid, long because of heated time during big production, it is easily generated by-product, as sent out
Raw elimination is reacted, and generates crotonbetaine etc.；(3) recrystallization isopropanol is solvent, and acetyl chloride is left
Carnitine dissolubility in isopropanol is low, affects recrystallization product quality.
The major impurity of document report is impurity A (crotonbetaine, (E)-or-(Z)-4-(trimethyl ammonium)-2-
Butenoic acid, structure below figure) and unreacted levocarnitine.
CN1408704A describes the preparation method of ALC: be dissolved in by levocarnitine inner salt
In glacial acetic acid, dropping chloroacetic chloride reacts, then low temperature crystallize, and 10% water-aqueous isopropanol recrystallization obtains
Highly finished product.Document adds p-methyl benzenesulfonic acid or DMAP makees catalyst, reaction can be improved
Yield.The shortcoming of this preparation method is: (1) adds catalyst can make the above-mentioned left card of product chlorinated acetyl
There is racemization in Ni Ting；(2) in acetic acid, ALC dissolubility is relatively big, and low temperature also is difficult to analysis
Crystalline substance, yield is the lowest；(3) the easy moisture absorption of ALC, easily dissolves in water, uses isopropanol
-water recrystallization yield is the lowest.
In view of the defect of above-mentioned document, CN102432483A is on the basis of CN1408704A, no
Add catalyst, use ethyl acetate crystallize after reaction, but purity and process for purification are not described.
CN103204782 describes the process for purification of ALC: with about 10 times amount (weight
Volume ratio) ether and oxolane mixed solution (1:4) heating for dissolving, then with n-butyl alcohol crystallize.Should
Technique there is the problem that solvent for use kind is too much, reclaims difficulty；Use inflammable and explosive ether.
The preparation condition that CN102557972 describes is roughly the same with CN102432483A, and simply crystallize is molten
Agent changes isopropanol, dehydrated alcohol or acetone into, but it still uses vacuum distillation recovered solvent, easily produces
Raw impurity A.Meanwhile, embodiment does not provide the detection data about impurity A, and through reality system
Standby, the yield of this patent is exaggerated, and is unable to reach its described degree at all.
Analysis result based on above-mentioned patent, the preparation of the ALC that prior art is reported
Method all has certain limitation and defect so that the synthesis technique repeatability described in patent is poor, miscellaneous
Matter A content is more.Application prospect in view of this ALC, it is provided that a kind of efficiently chlorination
The preparation method of acetyl levocarnitine, has with the biggest application prospect.
Summary of the invention
In view of this, it is an object of the invention to provide the preparation method of a kind of ALC,
Make described preparation method can reduce impurity A ((E)-or-(Z)-4-(trimethyl ammonium)-2-butylene acid) and
The content of unreacted raw material levocarnitine is all below 0.05%.
Further object is that the preparation method that a kind of ALC is provided so that
Described preparation method can make the content of ALC more than 99.90%.
For achieving the above object, the present invention provides following technical scheme:
The preparation method of a kind of ALC, comprises the following steps:
Step 1, levocarnitine and glacial acetic acid are mixed, drip excess acetyl chloride, after completion of the reaction under low temperature
Add the first solvent crystallization, filter, precipitate dried ALC crude product, described first
Solvent is 2-butanone, diisopropyl ether, acetonitrile or isopropyl acetate；
Step 2, in ALC crude product, add the second solvent, be heated to 40-60 DEG C, drip
Adding the 3rd solvent, filter after solid dissolves, filtrate slowly reduces temperature to room temperature, then low temperature crystallize,
Filtering, precipitate dried ALC fine work, described second solvent is dehydrated alcohol or first
Alcohol, described 3rd solvent is one or more in 2-butanone, isopropanol, isopropyl acetate.
For the defect of the post-processing operation in existing method, existing technique is caused to be easily generated impurity A and not
The raw material levocarnitine of reaction, the present invention uses suitable organic solvent to be combined using, to chlorination second
Acyl levocarnitine carries out separating and refining, and greatly reduces reduction impurity A and the left card of unreacted raw material
The content of Ni Ting, it is ensured that the purity of ALC is more than 99.90%.
Wherein, as preferably, the first solvent of the present invention is 2-butanone or isopropyl acetate；
As preferably, described second solvent is dehydrated alcohol, and the 3rd solvent is 2-butanone or is 2-fourth
Ketone 1 and the mixed solvent of isopropyl acetate；Further preferably, described 2-butanone and the body of isopropyl acetate
Long-pending ratio is 1:1.
As preferably, low temperature described in step 1 and step 2 is-20 DEG C～20 DEG C；It is further preferred that step
Rapid 1 and step 2 described in low temperature be-10 DEG C～0 DEG C.
As preferably, described in step 1, the temperature of reaction is 0 DEG C～100 DEG C；It is further preferred that step 1
The temperature of described reaction is 50 DEG C～60 DEG C.
As preferably, the mass volume ratio of levocarnitine described in step 1 and glacial acetic acid is 1g:3mL-10mL.
Further preferably；The mass volume ratio of levocarnitine and glacial acetic acid is 1g:3mL-6mL.
As preferably, the mol ratio of levocarnitine described in step 1 and chloroacetic chloride is 1:1-2；Further preferably
Ground, the mol ratio of levocarnitine and chloroacetic chloride is 1:1.1-1.3.
As preferably, the mass volume ratio of levocarnitine described in step 1 and the first solvent is
1g:20mL-25mL。
As preferably, described in step 2, the volume ratio of the second solvent and the 3rd solvent is 1:1-10；Further
The volume ratio being preferably the second solvent and the 3rd solvent is 1:3-5
As preferably, ALC crude product described in step 2 and the mass volume ratio of the second solvent
For 1.2g:4.5mL-5mL.
Impurity A ((E)-or-(Z)-4-(trimethyl the ammonium)-2-butylene prepared according to preparation method of the present invention
Acid) and the content of unreacted raw material levocarnitine all below 0.05%, and ALC
Purity is all more than 99.90%, and yield reaches about 85%.Meanwhile, according to CN102557972A patent
Embodiment 1-embodiment 3 scheme prepares reference substance, uses HPLC condition identical with the present invention to detect, its
Containing of impurity A ((E)-or-(Z)-4-(trimethyl ammonium)-2-butylene acid) and unreacted raw material levocarnitine
Amount is 0.13-0.43% and 0.00%-0.48%, and ALC purity is 98.65%-99.11%,
Average yield is 82.4%.
From above technical scheme, the present invention uses multiple suitable organic solvent according to certain der group
Close and use, ALC is separated and refine, reduction impurity A and unreacted former
The content of material levocarnitine is all below 0.05%, and the ALC fine work purity of preparation reaches
More than 99.90%.
Detailed description of the invention
The invention discloses the preparation method of a kind of ALC, those skilled in the art are permissible
Use for reference present disclosure, be suitably modified technological parameter and realize.Special needs to be pointed out is, all similar replacing
Changing and change apparent to those skilled in the art, they are considered as being included in the present invention.
Preparation method of the present invention is described by preferred embodiment, and related personnel substantially can be not
In departing from present invention, spirit and scope, compound as herein described and preparation method are modified
Or suitably change and combination, realize and apply the technology of the present invention.
The HPLC detection following detection method of employing related in the embodiment of the present invention:
Chromatographic condition:
Chromatographic column: C18
Flowing phase: 0.05mol/L KH2PO4-acetonitrile (30:70)
Flow velocity: 1.0ml/min
Column temperature: 30 DEG C
Detection wavelength: 210nm
Algoscopy: take ALC highly finished product appropriate, make every milliliter with flowing phased soln and contain
The solution of 1mg.Take impurity A reference substance appropriate, add flowing phased soln and dilution make in every 1ml containing about
The reference substance solution of impurity A 4 μ g.Take levocarnitine reference substance appropriate, add flowing phased soln and dilute
Make the reference substance solution containing about levocarnitine 4 μ g in every 1ml.Take above-mentioned solution 20 μ g respectively to inject
Chromatograph of liquid, records chromatogram, 5 times of record chromatogram to main constituent peak retention time.Separating degree
More than 2.0, number of theoretical plate is all not less than 5000, calculates by external standard method.
Below in conjunction with embodiment, the present invention is expanded on further.
Embodiment 1: prepare ALC
50L reactor adds levocarnitine 1kg, glacial acetic acid 3.6L, drips chloroacetic chloride 0.58kg, drip and finish
Being warming up to 50～60 DEG C, HPLC monitoring reaction levocarnitine content, less than 3%, is cooled to room temperature, adds
2-butanone 20L ,-10 DEG C of crystallizes 8 hours, filter, are dried, obtain white solid 1.254kg, yield 84.3%.
10L reactor adds 1.2kg crude product, dehydrated alcohol 5L, is heated to 50 DEG C of stirring and dissolving, takes advantage of
Heat filtering, adds 2-butanone 25L, is slowly dropped to room temperature, then is cooled to-10 DEG C of stirrings 8 hours, filters,
Washing, is vacuum dried to obtain highly finished product about 1.014kg, yield 84.5%.
Detecting through HPLC, impurity A is 0.02%, and levocarnitine is 0.01%, acetyl chloride left card Buddhist nun
Spit of fland is 99.92%.
Embodiment 2: prepare ALC
50L reactor adds levocarnitine 1kg, glacial acetic acid 4.2L, drips chloroacetic chloride 0.56kg, drip and finish
Being warming up to 50～60 DEG C, HPLC monitoring reaction levocarnitine content, less than 5%, is cooled to room temperature, adds
Diisopropyl ether 23L ,-10 DEG C of crystallizes 8 hours, filter, are dried, obtain white solid 1.227kg, yield 82.5%.
10L reactor adds 1.2kg crude product, methanol 4.5L, is heated to 40 DEG C of stirring and dissolving, while hot
Filter, add isopropyl acetate 22.5L, be slowly dropped to room temperature, then be cooled to-10 DEG C of stirrings 8 hours,
Filter, washing, be vacuum dried to obtain highly finished product about 1.030kg, yield 85.8%.
Detecting through HPLC, impurity A is 0.04%, levocarnitine 0.03%, ALC
It is 99.90%.
Embodiment 3: prepare ALC
50L reactor adds levocarnitine 1kg, glacial acetic acid 4L, drips chloroacetic chloride 0.59kg, drip and finish
Being warming up to 50～60 DEG C, HPLC monitoring reaction levocarnitine content, less than 2%, is cooled to room temperature, adds
Acetonitrile 22L ,-10 DEG C of crystallizes 8 hours, filter, are dried, obtain white solid 1.266kg, yield 85.1%.
10L reactor adds 1.2kg crude product, dehydrated alcohol 4.8L, is heated to 60 DEG C of stirring and dissolving,
Filtered while hot, adds 2-butanone 24L, is slowly dropped to room temperature, then is cooled to-10 DEG C of stirrings 8 hours, mistake
Filter, washing, it is vacuum dried to obtain highly finished product about 1.022kg, yield 85.2%.
Detecting through HPLC, impurity A is 0.02%, and levocarnitine is 0.00%, the left card of acetyl chloride
Ni Ting is 99.93%.
Embodiment 4: prepare ALC
50L reactor adds levocarnitine 1kg, glacial acetic acid 3.8L, drips chloroacetic chloride 0.6kg, drip and finish
Being warming up to 50～60 DEG C, HPLC monitoring reaction levocarnitine content, less than 2%, is cooled to room temperature, adds
Isopropyl acetate 21L ,-10 DEG C of crystallizes 8 hours, filter, are dried, obtain white solid 1.278kg, yield
86%.
10L reactor adds 1.2kg crude product, dehydrated alcohol 5L, is heated to 45 DEG C of stirring and dissolving, takes advantage of
Heat filtering, adds 2-butanone 12.5L and isopropyl acetate 12.5L, is slowly dropped to room temperature, then is cooled to-10
DEG C stirring 8 hours, filter, washing, be vacuum dried to obtain highly finished product about 1.035kg, yield 86.3%.
Detecting through HPLC, impurity A is 0.02%, and levocarnitine is 0.01%, acetyl chloride left card Buddhist nun
Spit of fland is 99.91%.
Embodiment 5: preparation comparison ALC
Prepare reference substance according to CN102557972A patent Example 1-embodiment 3 scheme, use and this
Invent the detection of identical HPLC condition, its impurity A ((E)-or-(Z)-4-(trimethyl ammonium)-2-butylene acid) with
And the content of unreacted raw material levocarnitine is as follows:
Embodiment 1: impurity A is 0.43%, levocarnitine is 0.48%, and ALC is
98.65%, yield is 81.7%.
Embodiment 2: impurity A is 0.15%, levocarnitine is 0.20%, and ALC is
98.99%, yield is 83.2%.
Embodiment 3: impurity A is 0.13%, levocarnitine is 0.00%, and ALC is
99.11%, yield is 82.4%.
The above is only the preferred embodiment of the present invention, it is noted that general for the art
For logical technical staff, under the premise without departing from the principles of the invention, it is also possible to make some improvement and profit
Decorations, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (10)
1. the preparation method of an ALC, it is characterised in that comprise the following steps:
Step 1, levocarnitine and glacial acetic acid are mixed, drip excess acetyl chloride, after completion of the reaction under low temperature
Add the first solvent crystallization, filter, precipitate dried ALC crude product, described first
Solvent is 2-butanone, diisopropyl ether, acetonitrile or isopropyl acetate；
Step 2, in ALC crude product, add the second solvent, be heated to 40-60 DEG C, drip
Adding the 3rd solvent, filter after solid dissolves, filtrate slowly reduces temperature to room temperature, then low temperature crystallize,
Filtering, precipitate dried ALC fine work, described second solvent is dehydrated alcohol or first
Alcohol, described 3rd solvent is one or more in 2-butanone, isopropanol, isopropyl acetate.
Preparation method the most according to claim 1, it is characterised in that low described in step 1 and step 2
Temperature is-20 DEG C～0 DEG C.
Preparation method the most according to claim 2, it is characterised in that low described in step 1 and step 2
Temperature is-10 DEG C～0 DEG C.
Preparation method the most according to claim 1, it is characterised in that the temperature of reaction described in step 1
It it is 0 DEG C～100 DEG C.
Preparation method the most according to claim 1, it is characterised in that levocarnitine described in step 1 and
The mass volume ratio of glacial acetic acid is 1g:3mL-10mL.
Preparation method the most according to claim 1, it is characterised in that levocarnitine described in step 1 and
The mol ratio of chloroacetic chloride is 1:1-2.
Preparation method the most according to claim 1, it is characterised in that levocarnitine described in step 1 and
The mass volume ratio of the first solvent is 1g:20mL-25mL.
Preparation method the most according to claim 1, it is characterised in that the second solvent described in step 2 and
The volume ratio of the 3rd solvent is 1:1-10.
Preparation method the most according to claim 8, it is characterised in that the second solvent described in step 2 and
The volume ratio of the 3rd solvent is 1:3-5.
Preparation method the most according to claim 1, it is characterised in that acetyl chloride described in step 2
The mass volume ratio of levocarnitine crude product and the second solvent is 1.2g:4.5mL-5mL.
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| CN110801448A (en) * | 2019-12-03 | 2020-02-18 | 珠海亿邦制药有限责任公司 | Acetyl chloride levocarnitine for injection and preparation method thereof |
| CN115141112A (en) * | 2022-06-25 | 2022-10-04 | 东北制药集团股份有限公司 | Acetyl L-carnitine impurity, and preparation and detection methods and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102557972A (en) * | 2011-12-31 | 2012-07-11 | 南京海辰药业有限公司 | Polycrystal substance of acetyl chloride levocarnitine |
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| KR101168657B1 (en) * | 2010-06-01 | 2012-07-25 | 주식회사 셀트리온제약 | Acetyl-L-carnitine malate, process for preparing the same, and pharmaceutical composition comprising the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102557972A (en) * | 2011-12-31 | 2012-07-11 | 南京海辰药业有限公司 | Polycrystal substance of acetyl chloride levocarnitine |
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