CN102516105A - Preparation method of L-carnitine hydrochloride - Google Patents
Preparation method of L-carnitine hydrochloride Download PDFInfo
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- CN102516105A CN102516105A CN2011103970379A CN201110397037A CN102516105A CN 102516105 A CN102516105 A CN 102516105A CN 2011103970379 A CN2011103970379 A CN 2011103970379A CN 201110397037 A CN201110397037 A CN 201110397037A CN 102516105 A CN102516105 A CN 102516105A
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Abstract
The invention provides a preparation method of L-carnitine hydrochloride. The method comprises the following steps of: synthesizing L-cyanocarnitine chloride in one step by taking R-epoxy chloropropane, hydrocyanic acid and trimethylamine as raw materials under the action of a basic catalyst and under the condition that the reaction temperature is 0-150 DEG C, the reaction time is 0.5-36 hours and the reaction pressure is 0.05-2.0 MPa; distilling a reaction liquid and recovering residual raw materials and solvent; adding 31 percent by mass of concentrated hydrochloric acid; hydrolyzing by controlling the reaction temperature at 30-120 DEG C and the reaction time at 1-36 hours; cooling and crystalizing an L-carnitine hydrochloride solution generated by reacting; separating ammonium chloride serving as a byproduct out; concentrating a solution containing L-carnitine hydrochloride under reduced pressure; crystalizing by taking absolute ethyl alcohol as a solvent; and recrystallizing to obtain the L-carnitine hydrochloride. The method is convenient, easy and clean, and is convenient for industrial production.
Description
Technical field:
The present invention relates to a kind of preparation method of L-carnitine hydrochloride
Background technology:
Carnitine (Carnitine) claim carnitine, DL-carnitine chloride again.Carnitine is a non-protein amino acid, often exists with hydrochloride form.Carnitine has two kinds of optically active isomers, that is: L-carnitine, D-carnitine, and the two balanced mix obtains raceme DL-carnitine.Wherein, have only L-carnitine to have physiologically active, D-carnitine and DL-carnitine then can suppress the activity of carnitine Transacetylase (CAT) and carnitine acyltransferase (PTC), the metabolism of fat of block cell competitively.Therefore the carnitine that is used to eat as foodstuff additive, protective foods functional component and pharmaceuticals etc. only allows with L-carnitine promptly usually said L-carnitine.L-carnitine has its hydrochloride, tartrate and Hydrocerol A magnesium salts as commodity.
Usually, the compound method of L-carnitine mainly contains extraction method, chemosynthesis Split Method, chirality synthesis method and biological enzyme.Carnitine is prevalent in invertebrates and the vertebrates tissue, also is present in some plants and the mikrobe.In the kidney of animal, blood, be that content is more in the tissues such as stronger bone muscle tendon of the energy and heart particularly with fatty acid metabolism.Gule Witsch etc. just isolated L one carnitine early than 1905 from meat medicinal extract.The typical method that from biomaterial, separates L-carnitine is a nineteen fifty-two report such as Carter, but the step of extracting purifying is more multiple.In recent years still relevant for the report that from beef or cow's milk treatment solution, extracts L one carnitine.The biological enzyme cost is lower, non-environmental-pollution, but domesticly do not see that industrialization report is arranged, the butyrobetaine that typical production technique is a Switzerland Long Sha company is the whole-cell catalytic method of substrate.Domestic is main with chemical synthesis still, wherein, is that four kinds of synthesis techniques of starting raw material all exist complex technical process with ketene dimer, γ-halo acetyl triethyl, D-N.F,USP MANNITOL, semi-lactosi respectively; Yield is low; Quantity of three wastes is difficult to greatly handle, and the shortcoming that cost is high does not realize industrialization.Only having with the epoxy chloropropane is the suitability for industrialized production that the method for starting raw material has realized L-carnitine.
Traditional epoxy chloropropane method via Trimethylamine 99 open loop, the synthesizing chlorinated carnitine nitrile of sodium cyanide step of replacing, obtains carnitine hydrochloride through hydrochloric acid hydrolysis with the epoxy chloropropane raw material again, adds the fractionation of chiral reagent L one second phthalein glutaminate and makes L-carnitine hydrochloride.If the main raw material that adopts is that R-epoxy chloropropane can directly obtain L-carnitine hydrochloride.
Main raw material epoxy chloropropane, Trimethylamine 99, sodium cyanide that this method adopts are staple commodities, can buy from market easily, and domestic manufacturers all adopt this explained hereafter at present.Owing to use sodium cyanide, the cyanogen saliniferous waste water that contains that is difficult to avoid a large amount of produces, and the liquid waste disposal difficulty is very big.When separating, also will increase alcohol and analyse step, separate relatively difficulty, Atom economy is poor.
In addition, CN1634870 discloses a kind of carnitine new synthetic process, is to be raw material with by product dextrorotation carnitine useless in the industry; In the presence of acid; With the chiral acid is catalyzer, racemization reaction takes place in polar solvent obtain the DL carnitine, obtains L-carnitine through splitting.But building-up process is longer, and dextrorotation carnitine source is limited, is difficult to be applicable to production.CN1265092 is that raw material carries out following chemical reaction under given conditions with (S)-3-hydroxybutyrolactone: ring-opening reaction, the epoxidation reaction of chiral centre counter-rotating, and the nucleophilic substitution reaction of Trimethylamine 99.But (S)-3-hydroxybutyrolactone derives from the synthetic of epoxy chloropropane and sodium cyanide, still can not eliminate the treatment of cyanide waste water problem.
Summary of the invention:
The present invention is directed to the deficiency of prior art, the preparation method of L-carnitine hydrochloride of being convenient to suitability for industrialized production of a kind of convenience, simple and easy and cleaning is provided.
The preparation method of L-carnitine hydrochloride of the present invention is a raw material with R-epoxy chloropropane, prussic acid, Trimethylamine 99, under the alkaline catalysts effect; 0～150 ℃ of temperature of reaction, the reaction times is 0.5～36 hour, reaction pressure is next step synthetic L-carnitine nitrile chloride of condition of 0.05MPa～2.0MPa; After reaction solution reclaims excess raw material and solvent through distillation, the quality percentage composition of adding proportional quantity>31% concentrated hydrochloric acid, 30～120 ℃ of control reaction temperature; 1～36 hour reaction times was hydrolyzed; L-carnitine hydrochloride solution through reaction is generated carries out crystallisation by cooling, isolates by-product ammonium chloride, again the solution that contains L-carnitine hydrochloride is carried out concentrating under reduced pressure; Carry out crystallization with absolute ethyl alcohol as solvent, recrystallization promptly gets L-carnitine hydrochloride.
In the preparation of above-mentioned carnitine nitrile chloride, the mole proportioning of R-epoxy chloropropane and prussic acid, Trimethylamine 99 is 1: 1.00～2.00: 1.00～4.00.
Catalyzer in the preparation of above-mentioned carnitine nitrile chloride is oxide compound, oxyhydroxide, prussiate, the alkyl alcoholate of basic metal or earth alkali metal, the carbonate of basic metal or earth alkali metal
,And at least a in ammonia, amine and the quaternary ammonium hydroxide.
Above-mentioned catalyzer is at least a in secondary amine, tertiary amine, the Trimethylamine 99.
Above-mentioned catalyzer is Trimethylamine 99 preferably.
Temperature of reaction in the preparation of above-mentioned L-carnitine nitrile chloride is 20～100 ℃.
The mol ratio of L-carnitine nitrile chloride and concentrated hydrochloric acid is 1: 1.0～4.0 in the hydrolysis reaction of above-mentioned L-carnitine nitrile chloride.
In the hydrolysis reaction of above-mentioned L-carnitine nitrile chloride, for fear of side reaction, the temperature of reaction optimum is 50～100 ℃.
Reaction formula is following in the inventive method:
In a word, through with R-epoxy chloropropane, prussic acid, Trimethylamine 99 are raw material; The method of synthetic L-carnitine nitrile chloride prepares L-carnitine hydrochloride under catalyst action, this process can be cut down the consumption of raw materials greatly, has eliminated to contain the cyanogen brine waste in the traditional synthesis; Shorten the reaction times, the step that simplifies the operation improves the production unit utilization ratio; Convenient, simple and easy and the cleaning, be convenient to suitability for industrialized production.
Embodiment:
Embodiment 1: in autoclave pressure, drop into R-epoxy chloropropane 93.5g (1.00mol) successively, ethanol 200g, triethylamine 1.5g; Prussic acid 30.0g (1.11mol), Trimethylamine 99 88g (1.54mol) is warming up to 80 ℃ gradually; Keep-up pressure at 0.4MPa, reacted 6 hours, gas chromatographic detection shows that R-epoxy chloropropane transforms fully; HPLC measures L-carnitine nitrile chloride content, reaches 97.4 % in the productive rate of R-epoxy chloropropane L-carnitine nitrile chloride.Reaction finishes, and the Trimethylamine 99 ethanolic soln is reclaimed in distillation, with 100ml absolute ethanol washing solids, filters, and drying gets white crystal L-carnitine nitrile chloride 157.5g, and content 99.58% collects rate 88.2% with R-epoxy chloropropane.
Get above-mentioned L-carnitine nitrile chloride and add the reactor drum of taking back the stream prolong, (quality percentage composition 36.5% 2.54mol), slowly is warming up to 80 ℃ to add concentrated hydrochloric acid 254.0g; Insulation reaction 8 hours is cooled to 0 ℃, filters out ammonium chloride, and filter cake is with twice of 20ml methanol wash; Merging filtrate is evaporated to driedly, adds absolute ethyl alcohol 150g, and heating is dissolving fully; In filtrating, add gac 3g, 60 ℃ are incubated 1 hour, filter the filtrating crystallisation by cooling; Filter the gained crystal and carry out recrystallization with the 150g absolute ethyl alcohol, drying gets product L-carnitine hydrochloride 146.5g, collects rate 83.3% with L-carnitine nitrile chloride.
Embodiment 2: operation as catalyzer, is warming up to 60 ℃ with Trimethylamine 99 self with embodiment 1 gradually; Keep-up pressure at 0.5MPa; Reacted 6 hours, after reaction finished, gas chromatographic detection showed that R-epoxy chloropropane transforms fully; HPLC measures L-carnitine nitrile chloride content, reaches 99.8 % in the productive rate of R-epoxy chloropropane L-carnitine nitrile chloride.The Trimethylamine 99 ethanolic soln is reclaimed in distillation, with 100ml absolute ethyl alcohol wash-out solids, filters, and drying gets white crystal L-carnitine nitrile chloride 161.2g, and content 99.21% collects rate 91.0% with R-epoxy chloropropane.
Get above-mentioned L-carnitine nitrile chloride and add the reactor drum of taking back the stream prolong, and adding concentrated hydrochloric acid 254.0g (36.5%, 2.54mol), slowly be warming up to 80 ℃; Insulation reaction 8 hours is cooled to 0 ℃, filters out ammonium chloride, and filter cake is with twice of 20ml methanol wash; Merging filtrate is evaporated to driedly, adds absolute ethyl alcohol 150g, and heating is dissolving fully; In filtrating, add gac 3g, 60 ℃ are incubated 1 hour, filter the filtrating crystallisation by cooling; Filter the gained crystal and carry out recrystallization with the 150g absolute ethyl alcohol, drying gets product L-carnitine hydrochloride 151.9g, collects rate 84.5% with L-carnitine nitrile chloride.
Embodiment 3: operation is with embodiment 1, and using Diisopropylamine 1.5g instead is catalyzer, is warming up to 90 ℃ gradually; Keep-up pressure at 0.4MPa; Reacted 8 hours, after reaction finished, gas chromatographic detection showed that R-epoxy chloropropane transforms fully; HPLC measures L-carnitine nitrile chloride content, reaches 93.7 % in the productive rate of R-epoxy chloropropane L-carnitine nitrile chloride.The Trimethylamine 99 ethanolic soln is reclaimed in distillation, with 100ml absolute ethyl alcohol wash-out solids, filters, and drying gets white crystal carnitine nitrile chloride 140.7g content 99.35%, collects rate 78.3% with R-epoxy chloropropane.
L-carnitine nitrile chloride hydrolysis is operated with embodiment 2, and adding concentrated hydrochloric acid 234.5g (36.5%, 2.35mol), slowly be warming up to 80 ℃; Insulation reaction 8 hours is cooled to 0 ℃, filters out ammonium chloride, and filter cake is with twice of 20ml methanol wash; Merging filtrate is evaporated to driedly, adds absolute ethyl alcohol 150g, and heating is dissolving fully; In filtrating, add gac 3g, 60 ℃ are incubated 1 hour, filter the filtrating crystallisation by cooling; Filter the gained crystal and carry out recrystallization with the 150g absolute ethyl alcohol, drying gets product L-carnitine hydrochloride 128.6g, collects rate 82.6% with L-carnitine nitrile chloride.
Embodiment 4: in autoclave pressure, drop into R-epoxy chloropropane 93.5g (1.00mol) successively, methyl alcohol 200g, prussic acid 30.0g (1.11mol); Trimethylamine 99 88g (1.54mol) is warming up to 60 ℃ gradually, keep-ups pressure at 0.5MPa; Reacted 6 hours, after reaction finished, gas chromatographic detection showed that R-epoxy chloropropane transforms fully; HPLC measures L-carnitine nitrile chloride content, reaches 95.4 % in the productive rate of R-epoxy chloropropane L-carnitine nitrile chloride.The Trimethylamine 99 methanol solution is reclaimed in distillation, in distillation residue directly adding concentrated hydrochloric acid 300g (36.5%, 3.00mol), slowly be warming up to 80 ℃; Insulation reaction 8 hours is cooled to 0 ℃, filters out ammonium chloride, and filter cake is with twice of 20ml methanol wash; Merging filtrate adds gac in filtrating, 80 ℃ are incubated 1 hour, filter; Filtrate decompression is concentrated into dried, adds absolute ethyl alcohol 150g, and heating is dissolving fully, crystallisation by cooling; Filter the gained crystal and carry out recrystallization with the 150g absolute ethyl alcohol, drying gets product L-carnitine hydrochloride 128.4g, collects rate 65.1% with R-epoxy chloropropane.
The foregoing description is that foregoing of the present invention is further described, but should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to the foregoing description.All technology that realizes based on foregoing all belong to scope of the present invention.
Claims (7)
1.L the preparation method of-carnitine hydrochloride, this method are to be raw material with R-epoxy chloropropane, prussic acid, Trimethylamine 99, under the alkaline catalysts effect; 0～150 ℃ of temperature of reaction, the reaction times is 0.5～36 hour, reaction pressure is next step synthetic L-carnitine nitrile chloride of condition of 0.05MPa～2.0MPa; After reaction solution reclaims excess raw material and solvent through distillation, adding quality percentage composition>31% concentrated hydrochloric acid, 30～120 ℃ of control reaction temperature; 1～36 hour reaction times was hydrolyzed; L-carnitine hydrochloride solution through reaction is generated carries out crystallisation by cooling, isolates by-product ammonium chloride, again the solution that contains L-carnitine hydrochloride is carried out concentrating under reduced pressure; Carry out crystallization with absolute ethyl alcohol as solvent, recrystallization promptly gets L-carnitine hydrochloride.
2. the preparation method of L-carnitine hydrochloride as claimed in claim 1, the mole proportioning that it is characterized in that R-epoxy chloropropane and prussic acid, Trimethylamine 99 is 1: 1.00～2.00: 1.00～4.00.
3. according to claim 1 or claim 2 the preparation method of L-carnitine hydrochloride; It is characterized in that catalyzer is oxide compound, oxyhydroxide, prussiate, the alkyl alcoholate of basic metal or earth alkali metal; The carbonate of basic metal or earth alkali metal, and at least a in ammonia, amine and the quaternary ammonium hydroxide.
4. the preparation method of L-carnitine hydrochloride as claimed in claim 3 is characterized in that catalyzer is at least a in secondary amine, tertiary amine, the Trimethylamine 99.
5. according to claim 1 or claim 2 the preparation method of L-carnitine hydrochloride is characterized in that the temperature of reaction in the preparation of L-carnitine nitrile chloride is 20～100 ℃.
6. according to claim 1 or claim 2 the preparation method of L-carnitine hydrochloride is characterized in that the mol ratio of L-carnitine nitrile chloride and concentrated hydrochloric acid is 1: 1.0～4.0 in the hydrolysis reaction of L-carnitine nitrile chloride.
7. according to claim 1 or claim 2 the preparation method of L-carnitine hydrochloride is characterized in that in the hydrolysis reaction of L-carnitine nitrile chloride that temperature of reaction is 50～100 ℃.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383741A (en) * | 2018-03-16 | 2018-08-10 | 开原亨泰化工有限公司 | It is a kind of to prepare new method of the l-cn at salt |
| CN108484441A (en) * | 2018-05-15 | 2018-09-04 | 常州兰陵制药有限公司 | Levocarnitine intermediate L-（-）The synthetic method of chlorination 3- cyano -2- hydroxypropyl trimethylammonium amine |
| CN108727221A (en) * | 2018-05-31 | 2018-11-02 | 常州兰陵制药有限公司 | The preparation method of levocarnitine intermediate |
| CN110003032A (en) * | 2019-04-29 | 2019-07-12 | 诚达药业股份有限公司 | A kind of continuous preparation method of L-carnitine |
| CN114084893A (en) * | 2021-11-26 | 2022-02-25 | 开原亨泰营养科技有限公司 | Harmless treatment method for cyanide in waste salt in L-carnitine production process |
| CN114436872A (en) * | 2022-02-22 | 2022-05-06 | 华今(山东)新材料科技有限公司 | Low-cost L-carnitine preparation method |
| CN115650868A (en) * | 2022-10-20 | 2023-01-31 | 安徽泰格生物科技有限公司 | Preparation method of L-carnitine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01139559A (en) * | 1987-11-25 | 1989-06-01 | Earth Chem Corp Ltd | Production of 4-chloro-3-hydroxybutyronitrile |
-
2011
- 2011-12-05 CN CN201110397037.9A patent/CN102516105B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01139559A (en) * | 1987-11-25 | 1989-06-01 | Earth Chem Corp Ltd | Production of 4-chloro-3-hydroxybutyronitrile |
Non-Patent Citations (1)
| Title |
|---|
| 肖鉴谋: "L-肉碱盐酸盐的制备研究", 《化学世界》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383741A (en) * | 2018-03-16 | 2018-08-10 | 开原亨泰化工有限公司 | It is a kind of to prepare new method of the l-cn at salt |
| CN108484441A (en) * | 2018-05-15 | 2018-09-04 | 常州兰陵制药有限公司 | Levocarnitine intermediate L-（-）The synthetic method of chlorination 3- cyano -2- hydroxypropyl trimethylammonium amine |
| CN108727221A (en) * | 2018-05-31 | 2018-11-02 | 常州兰陵制药有限公司 | The preparation method of levocarnitine intermediate |
| CN110003032A (en) * | 2019-04-29 | 2019-07-12 | 诚达药业股份有限公司 | A kind of continuous preparation method of L-carnitine |
| CN110003032B (en) * | 2019-04-29 | 2022-05-24 | 诚达药业股份有限公司 | Continuous preparation method of L-carnitine |
| CN114084893A (en) * | 2021-11-26 | 2022-02-25 | 开原亨泰营养科技有限公司 | Harmless treatment method for cyanide in waste salt in L-carnitine production process |
| CN114436872A (en) * | 2022-02-22 | 2022-05-06 | 华今(山东)新材料科技有限公司 | Low-cost L-carnitine preparation method |
| CN114436872B (en) * | 2022-02-22 | 2023-08-18 | 华今(山东)新材料科技有限公司 | Low-cost preparation method of L-carnitine |
| CN115650868A (en) * | 2022-10-20 | 2023-01-31 | 安徽泰格生物科技有限公司 | Preparation method of L-carnitine |
| CN115650868B (en) * | 2022-10-20 | 2024-01-26 | 安徽泰格生物科技有限公司 | Preparation method of L-carnitine |
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