CN104163769A - Preparation method of propionyl levocarnitine hydrochloride - Google Patents
Preparation method of propionyl levocarnitine hydrochloride Download PDFInfo
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- CN104163769A CN104163769A CN201410282762.5A CN201410282762A CN104163769A CN 104163769 A CN104163769 A CN 104163769A CN 201410282762 A CN201410282762 A CN 201410282762A CN 104163769 A CN104163769 A CN 104163769A
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Abstract
The invention relates to the field of pharmaceutical preparations, and specifically relates to a preparation method of propionyl levocarnitine hydrochloride. The preparation method comprises the steps of mixing levocarnitine with propionic acid; dropwise adding propionyl chloride for reaction; adding a first solvent for crystallization at a low temperature after the reaction is finished; filtering; drying a precipitate to obtain a propionyl levocarnitine hydrochloride crude product; adding a second solvent to the crude product; heating; dropwise adding a third solvent; filtering after solid is dissolved; cooling a filtrate to a room temperature slowly; crystallizing at a low temperature; filtering; and drying the precipitate to obtain a propionyl levocarnitine hydrochloride purified product. The preparation method separates and purifies propionyl levocarnitine hydrochloride by combining a plurality of appropriate organic solvents according to a certain sequence, and reduces the content of impurity A and unreacted raw material of levocarnitine to below 0.05%. The purity of the prepared propionyl levocarnitine hydrochloride purified product is higher than 99.90%.
Description
Technical field
The present invention relates to field of medicine preparations, be specifically related to a kind of preparation method of chlorination propionyl-L-carnitine.
Background technology
Levocarnitine; chemistry (R)-3-carboxyl-2-hydroxy-n by name; N; N-trimethylammonium propanaminium hydroxide inner salt; be the interior crude substance of body essential in Mammals energy metabolism, it can bring longer chain fatty acid into mitochondrial matrix, and promotes its oxygenolysis; for cell provides energy, again can be by the short chain fatty acyl group output producing in plastosome.Levocarnitine can also increase the activity of Reduced nicotinamide-adenine dinucleotide (NADH) cell C pigment reductase enzyme, Terminal oxidase, the generation of acceleration adenosine triphyosphate (ATP), participates in the detoxification of some drugs.Levocarnitine also can be alleviated it because lacking the fat metabolic disturbance causing in body, is especially myocardial cell's main energy derive of muscle cell.
The chemical structure of levocarnitine is shown below:
Chlorination propionyl-L-carnitine (Propionyl Levocarnitine Hydrochloride, PLC), chemistry (R)-4-(N by name, N, N-trimethylammonium is amino)-3-propionyloxy butyrates hydrochlorate, be the derivative of levocarnitine, in oxidative metabolism, play an important role.Similar with levocarnitine, the effect of chlorination propionyl-L-carnitine anti-ischemia is relevant with the ability of its buffering long-chain aliphatic alcohol ester, and chlorination propionyl-L-carnitine is more easily through myocardial cell, acts on and is better than levocarnitine.Chlorination propionyl-L-carnitine can also change lipid metabolism, and the generation of cyclooxygenase and lipoxidase is carried out to regular adjusting, promotes the generation of anti-inflammatory, protection blood vessel and anticoagulin.
Chlorination propionyl-L-carnitine is developed by Italian Sigma-Taug company the earliest, listing in 1985, indication is treatment senile dementia, country's listings such as later Xiang Xu Britain, Argentina, Korea S, and indication has treatment melancholia and Alzheimer's disease etc.Chlorination propionyl-L-carnitine can also become and chronic heart failure for lumen of artery internal congestion venereal disease, improves the tolerance of body to physical exertion.
The structure of chlorination propionyl-L-carnitine is shown below:
Chlorination propionyl-L-carnitine is white crystal, in water, methyl alcohol, very easily dissolves, easily molten in ethanol, propionic acid, almost insoluble in ether, ethyl acetate, acetone, chloroform.At present, existing multiple open method is for the preparation of chlorination propionyl-L-carnitine, and general method is to take levocarnitine as raw material, and in certain solvent, reaction prepares with propionyl chloride, and synthetic method is as follows:
Levocarnitine is soluble in water, methyl alcohol and ethanol etc., is insoluble in acetone, is insoluble to trichloromethane.Solvability based on levocarnitine, the synthetic method of the chlorination propionyl-L-carnitine of US4443475 report is that levocarnitine is dissolved in trifluoroacetic acid, drips propionyl chloride, in 40～50 ℃ of reactions, prepares.But make solvent with trifluoroacetic acid, cost is high, to pollute and weigh, operational danger is large.
CN1651402A has reported take propionic acid as solvent, add p-methyl benzenesulfonic acid to make catalyzer, can obtain chlorination propionyl-L-carnitine crude product by high yield, but in patent, do not mention the purity of crude product, and existing patent CN102391141A mentions and adds this catalyzer can make above-mentioned product generation racemization, and may have the residual of catalyzer.
The disclosed technical scheme of CN1995010A is that levocarnitine is dissolved in propionic acid, drips propionyl chloride reaction, does not add catalyzer, and the method is used propionic acid to make solvent, can overcome the disadvantage in aforesaid method.
Because chlorination propionyl-L-carnitine solubleness in propionic acid is larger, low temperature is also difficult to crystallization, CN1995010A aftertreatment adopts first underpressure distillation to reclaim excessive propionyl chloride and solvent propionic acid, add again acetone crystallization, but existing patent CN1408704A mention CN1995010A when underpressure distillation because heated time is long, easily produce impurity.The major impurity of bibliographical information for dehydration impurity A ((E)-or-(Z)-4-(trimethylammonium ammonium)-2-butylene acid, structure is as figure below) and unreacted raw material levocarnitine.
In addition, the yield that the disclosed technical scheme of CN1995010A is recorded in original text can reach more than 90%, but through actual preparation, its yield only can reach 60% left and right.And the propionyl-L-carnitine HPLC content detection value in CN1995010A the disclosed embodiments 2 has surpassed 100%, this does not conform to objective circumstances, and the yield of embodiment 3 calculates and also do not reach 94.3% at all according to the data of its record.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of preparation method of chlorination propionyl-L-carnitine, make content that described preparation method can reduce impurity A ((E)-or-(Z)-4-(trimethylammonium ammonium)-2-butylene acid) and unreacted raw material levocarnitine all below 0.05%.
Another object of the present invention is to provide a kind of preparation method of chlorination propionyl-L-carnitine, makes described preparation method can make the content of chlorination propionyl-L-carnitine more than 99.90%.
For achieving the above object, the invention provides following technical scheme:
A preparation method for chlorination propionyl-L-carnitine, comprises the following steps:
Step 1, levocarnitine and propionic acid are mixed, the reaction of dropping propionyl chloride, under low temperature, add after completion of the reaction the first solvent crystallization, filter, after precipitation is dry, obtain chlorination propionyl-L-carnitine crude product, described the first solvent is methyl tertiary butyl ether, isopropyl ether, acetonitrile, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane;
Step 2, in chlorination propionyl-L-carnitine crude product, add the second solvent, be heated to 45-65 ℃, drip the 3rd solvent, after dissolution of solid, filter, filtrate is slowly reduced temperature to room temperature, then low temperature crystallization, filter, after precipitation is dry, obtain chlorination propionyl-L-carnitine fine work, described the second solvent is one or more in Virahol, methyl tertbutyl ketone, isopropyl acetate, and described the 3rd solvent is dehydrated alcohol or methyl alcohol.
Defect for the post-processing operation in existing method, cause existing technique easily to produce impurity A and unreacted raw material levocarnitine, the present invention adopts suitable organic solvent to be used in combination, chlorination propionyl-L-carnitine is carried out to separation and refining, greatly reduce the content of impurity A and unreacted raw material levocarnitine, guarantee that the purity of chlorination propionyl-L-carnitine is more than 99.90%.
Wherein, as preferably, the first solvent of the present invention is methyl tertiary butyl ether or isopropyl ether;
As preferably, described the second solvent is a kind of in Virahol, methyl tertbutyl ketone, isopropyl acetate, or is Virahol and isopropyl acetate mixed solvent, or is methyl tertbutyl ketone and isopropyl acetate mixed solvent; Further preferably, in described Virahol and isopropyl acetate mixed solvent, the volume of Virahol and isopropyl acetate is 1:3, and in described methyl tertbutyl ketone and isopropyl acetate mixed solvent, the volume ratio of methyl tertbutyl ketone and isopropyl acetate is 2:3.
As preferably, low temperature is-20 ℃～20 ℃ described in step 1 and step 2; Further preferably, described in step 1 and step 2, low temperature is-5 ℃～5 ℃; More preferably, described in step 1 and step 2, low temperature is-5 ℃～0 ℃
As preferably, the temperature of reaction is 0 ℃～100 ℃ described in step 1; Further preferably, described in step 1, the temperature of reaction is 40 ℃～50 ℃.
As preferably, the mass volume ratio of levocarnitine and propionic acid is 1g:1mL-10mL described in step 1.Further preferably; The mass volume ratio of levocarnitine and propionic acid is 1g:3mL-4mL.
As preferably, the mol ratio of levocarnitine and propionyl chloride is 1:1-2 described in step 1; Further preferably, the mol ratio of levocarnitine and propionyl chloride is 1:1-1.5.
As preferably, the mass volume ratio of levocarnitine and the first solvent is 1g:5mL-10mL described in step 1.
As preferably, the volume ratio of the second solvent and the 3rd solvent is 1-10:1 described in step 2; More preferably the volume ratio of the second solvent and the 3rd solvent is 1-3:1
As preferably, the mass volume ratio of chlorination propionyl-L-carnitine crude product and the second solvent is 4g:3mL-5mL described in step 2.
The content of the impurity A of preparing according to preparation method of the present invention ((E)-or-(Z)-4-(trimethylammonium ammonium)-2-butylene acid) and unreacted raw material levocarnitine is all below 0.05%, and chlorination propionyl-L-carnitine purity is all more than 99.90%, and yield reaches more than 80%.Simultaneously, according to CN1995010A patent working example 1-embodiment 3 schemes, prepare reference substance, adopt HPLC condition identical with the present invention to detect, its impurity A ((E)-or-(Z)-4-(trimethylammonium ammonium)-2-butylene acid) and the content of unreacted raw material levocarnitine are more than 0.05%, content is below 99.83%, and yield is below 62.8%.
In addition, the present invention has also carried out transposing simultaneous test to the addition sequence of described the second solvent and the 3rd solvent, result shows, first add the 3rd dissolution with solvents crude product, required quantity of solvent is more, directly cause adding the second more a large amount of solvents by product crystallization, not only improved solvent cost, and yield is also lower, far below 80%: and for the ease of the second solvent crystallization, deliberately reduce by first quantity of solvent of dissolving crude product, can cause solution thickness, filtration difficulty, cannot proceed subsequent operations.
From above technical scheme, the present invention adopts multiple suitable organic solvent to use according to certain sequential combination, chlorination propionyl-L-carnitine is carried out to separation and refining, reduce the content of impurity A and unreacted raw material levocarnitine all below 0.05%, the chlorination propionyl-L-carnitine fine work purity of preparation reaches more than 99.90%.
Accompanying drawing explanation
Figure 1 shows that the HPLC spectrogram of impurity A reference substance in embodiment 1;
Figure 2 shows that the HPLC spectrogram of levocarnitine reference substance in embodiment 1;
Figure 3 shows that the HPLC spectrogram of chlorination propionyl-L-carnitine fine work in embodiment 1.
Embodiment
The invention discloses a kind of preparation method of chlorination propionyl-L-carnitine, those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Preparation method of the present invention is described by preferred embodiment, related personnel obviously can be within not departing from content of the present invention, spirit and scope to compound as herein described with preparation method changes or suitably change and combination, realize and apply the technology of the present invention.
The HPLC relating in the embodiment of the present invention detects and adopts following detection method:
Chromatographic condition:
Chromatographic column: C18
Moving phase: 0.05mol/L KH
2pO
4-acetonitrile (30:70)
Flow velocity: 1.0ml/min
Column temperature: 30 ℃
Detect wavelength: 210nm
Assay method: get chlorination propionyl-L-carnitine highly finished product appropriate, dissolve and make every milliliter containing the solution of 1mg by moving phase.Get impurity A reference substance appropriate, add moving phase and dissolve and dilute the reference substance solution of making approximately impure A 4 μ g in every 1ml.Get levocarnitine reference substance appropriate, add moving phase and dissolve and dilute the reference substance solution of making in every 1ml approximately containing levocarnitine 4 μ g.Get respectively above-mentioned solution 20 μ g injection liquid chromatographies, record color atlas, record color atlas to 5 times of principal constituent peak retention time.Resolution is greater than 2.0, and number of theoretical plate is all not less than 5000, by external standard method, calculates.
Below in conjunction with embodiment, further set forth the present invention.
Embodiment 1: preparation chlorination propionyl-L-carnitine
Get levocarnitine 100g, add anhydrous propionic acid 300ml, drip propionyl chloride 68.8g, drip to finish and be warming up to 40～50 ℃, HPLC monitoring reacts completely, and is cooled to room temperature, adds methyl tertiary butyl ether 600ml ,-5 ℃ of-0 ℃ of crystallizatioies 6 hours, filter, dry, obtain white solid 130.9g, yield 83.2%.
120g crude product is added in methyl tertbutyl ketone 1000ml, and stirring and evenly mixing, is heated to 55 ℃, drips 500ml dehydrated alcohol, dissolution of solid, filtered while hot, is down to room temperature, is cooled to-5 ℃-0 ℃ and stirs 8 hours, filter, washing, vacuum-drying obtains the about 100g of highly finished product, yield 83.3%.
Through HPLC, detect, impurity A is 0.05%, and levocarnitine is 0.03%, and chlorination propionyl-L-carnitine is 99.92%.
Embodiment 2: preparation chlorination propionyl-L-carnitine
Get levocarnitine 100g, add anhydrous propionic acid 400ml, drip propionyl chloride 68.8g, drip to finish and be warming up to 40～50 ℃, HPLC monitoring reacts completely, be cooled to room temperature, add Isosorbide-5-Nitrae-dioxane 800ml ,-5 ℃ of-0 ℃ of crystallizatioies 6 hours, filter, dry, obtain white solid 126.2g, yield 81.2%.
120g crude product is added in Virahol 900ml, and stirring and evenly mixing, is heated to 45 ℃, drips 300ml dehydrated alcohol, dissolution of solid, filtered while hot, is down to room temperature, is cooled to-5 ℃-0 ℃ and stirs 8 hours, filter, washing, vacuum-drying obtains the about 95.5g of highly finished product, yield 79.6%.
Through HPLC, detect, impurity A is 0.03%, and levocarnitine does not detect, and chlorination propionyl-L-carnitine is 99.90%.
Embodiment 3: preparation chlorination propionyl-L-carnitine
Get levocarnitine 100g, add anhydrous propionic acid 300ml, drip propionyl chloride 74.6g, drip to finish and be warming up to 40～50 ℃, HPLC monitoring reacts completely, and is cooled to room temperature, adds acetonitrile 600ml ,-5 ℃ of-0 ℃ of crystallizatioies 6 hours, filter, dry, obtain white solid 130.2g, yield 82.7%.
120g crude product is added in isopropyl acetate 1500ml, and stirring and evenly mixing, is heated to 65 ℃, drips 500ml dehydrated alcohol, dissolution of solid, filtered while hot, is down to room temperature, is cooled to-5 ℃-0 ℃ and stirs 8 hours, filter, washing, vacuum-drying obtains the about 100.8g of highly finished product, yield 84%.
Through HPLC, detect, impurity A is 0.05%, and levocarnitine is 0.02%, and chlorination propionyl-L-carnitine is 99.91%.
Embodiment 4: preparation chlorination propionyl-L-carnitine
Get levocarnitine 100g, add anhydrous propionic acid 400ml, drip propionyl chloride 86g, drip to finish and be warming up to 40～50 ℃, HPLC monitoring reacts completely, and is cooled to room temperature, adds tetrahydrofuran (THF) 1000ml ,-5 ℃ of-0 ℃ of crystallizatioies 6 hours, filter, dry, obtain white solid 131.4g, yield: 83.5%.
120g crude product is added in methyl tertbutyl ketone-isopropyl acetate (2:3) 1000ml, stirring and evenly mixing, is heated to 50 ℃, drips 400ml dehydrated alcohol, dissolution of solid, filtered while hot, is down to room temperature, is cooled to-5 ℃-0 ℃ and stirs 8 hours, filter, washing, vacuum-drying obtains the about 104.2g of highly finished product, yield approximately 86.8%.
Through HPLC, detect, impurity A is 0.03%, and levocarnitine is 0.03%, and chlorination propionyl-L-carnitine is 99.93%.
Embodiment 5: preparation chlorination propionyl-L-carnitine
Get levocarnitine 100g, add anhydrous propionic acid 300ml, drip propionyl chloride 68.8g, drip to finish and be warming up to 40～50 ℃, HPLC monitoring reacts completely, and is cooled to room temperature, adds isopropyl ether 600ml ,-5 ℃ of-0 ℃ of crystallizatioies 6 hours, filter, dry, obtain white solid 121.8g, yield 77.4%.
120g crude product is added in Virahol-isopropyl acetate (1:3) 1000ml, and stirring and evenly mixing, is heated to 60 ℃, drips 400ml methyl alcohol, dissolution of solid, filtered while hot, is down to room temperature, is cooled to-5 ℃-0 ℃ and stirs 8 hours, filter, washing, vacuum-drying obtains the about 98g of highly finished product, yield 81.7%.
Through HPLC, detect, impurity A is 0.05%, and levocarnitine is 0.02%, and chlorination propionyl-L-carnitine is 99.91%.
Embodiment 6: preparation contrast chlorination propionyl-L-carnitine
According to CN1995010A patent working example 1-embodiment 3 schemes, prepare reference substance, adopt HPLC condition identical with the present invention to detect, its impurity A ((E)-or-acid of (Z)-4-(trimethylammonium ammonium)-2-butylene) and the content of unreacted raw material levocarnitine are as follows:
Embodiment 1: impurity A is 0.09%, and levocarnitine is 0.07%, and chlorination propionyl-L-carnitine is 99.81%, and yield is 61.6%.
Embodiment 2: impurity A is 0.08%, and levocarnitine is 0.06%, and chlorination propionyl-L-carnitine is 99.83%, and yield is 62.8%.
Embodiment 3: impurity A is 0.08%, and levocarnitine is 0.05%, and chlorination propionyl-L-carnitine is 99.80%, and yield is 58.8%.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a preparation method for chlorination propionyl-L-carnitine, is characterized in that, comprises the following steps:
Step 1, levocarnitine and propionic acid are mixed, the reaction of dropping propionyl chloride, under low temperature, add after completion of the reaction the first solvent crystallization, filter, after precipitation is dry, obtain chlorination propionyl-L-carnitine crude product, described the first solvent is methyl tertiary butyl ether, isopropyl ether, acetonitrile, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane;
Step 2, in chlorination propionyl-L-carnitine crude product, add the second solvent, be heated to 45-65 ℃, drip the 3rd solvent, after dissolution of solid, filter, filtrate is slowly reduced temperature to room temperature, then low temperature crystallization, filter, after precipitation is dry, obtain chlorination propionyl-L-carnitine fine work, described the second solvent is one or more in Virahol, methyl tertbutyl ketone, isopropyl acetate, and described the 3rd solvent is dehydrated alcohol or methyl alcohol.
2. preparation method according to claim 1, is characterized in that, low temperature is-20 ℃～20 ℃ described in step 1 and step 2.
3. preparation method according to claim 2, is characterized in that, low temperature is-5 ℃～5 ℃ described in step 1 and step 2.
4. preparation method according to claim 1, is characterized in that, the temperature of reaction is 0 ℃～100 ℃ described in step 1.
5. preparation method according to claim 1, is characterized in that, the mass volume ratio of levocarnitine and propionic acid is 1g:1mL-10mL described in step 1.
6. preparation method according to claim 1, is characterized in that, the mol ratio of levocarnitine and propionyl chloride is 1:1-2 described in step 1.
7. preparation method according to claim 1, is characterized in that, the mass volume ratio of levocarnitine and the first solvent is 1g:5mL-10mL described in step 1.
8. preparation method according to claim 1, is characterized in that, the volume ratio of the second solvent and the 3rd solvent is 1-10:1 described in step 2.
9. preparation method according to claim 8, is characterized in that, the volume ratio of the second solvent and the 3rd solvent is 1-3:1 described in step 2.
10. preparation method according to claim 1, is characterized in that, the mass volume ratio of chlorination propionyl-L-carnitine crude product and the second solvent is 4g:3mL-5mL described in step 2.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111100024A (en) * | 2019-12-25 | 2020-05-05 | 南京谱利健生物技术有限公司 | Method for preparing stable isotope labeled acyl carnitine |
| CN112379016A (en) * | 2020-11-02 | 2021-02-19 | 江苏宝众宝达药业有限公司 | Method for measuring content of L-carnitine in 3-O-lauroyl-L-carnitine by high performance liquid chromatography |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4443475A (en) * | 1979-04-23 | 1984-04-17 | Claudio Cavazza | Amides of acyl-carnitines, process for preparing same and pharmaceutical compositions containing such amides |
| CN1995010A (en) * | 2006-12-29 | 2007-07-11 | 沈阳东宇精细化工有限公司 | Method for synthesizing propionyl levo-carnitine hydrochlorate |
-
2014
- 2014-06-23 CN CN201410282762.5A patent/CN104163769B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4443475A (en) * | 1979-04-23 | 1984-04-17 | Claudio Cavazza | Amides of acyl-carnitines, process for preparing same and pharmaceutical compositions containing such amides |
| CN1995010A (en) * | 2006-12-29 | 2007-07-11 | 沈阳东宇精细化工有限公司 | Method for synthesizing propionyl levo-carnitine hydrochlorate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111100024A (en) * | 2019-12-25 | 2020-05-05 | 南京谱利健生物技术有限公司 | Method for preparing stable isotope labeled acyl carnitine |
| CN112379016A (en) * | 2020-11-02 | 2021-02-19 | 江苏宝众宝达药业有限公司 | Method for measuring content of L-carnitine in 3-O-lauroyl-L-carnitine by high performance liquid chromatography |
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