CN106045919B - Preparation method of L-carnitine orotate - Google Patents
Preparation method of L-carnitine orotate Download PDFInfo
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- CN106045919B CN106045919B CN201610528724.2A CN201610528724A CN106045919B CN 106045919 B CN106045919 B CN 106045919B CN 201610528724 A CN201610528724 A CN 201610528724A CN 106045919 B CN106045919 B CN 106045919B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
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Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of L-carnitine orotate, which comprises the following steps: step a, reacting orotic acid with ammonia to generate orotic acid ammonium salt; step b, reacting orotate ammonium salt with L-carnitine in an aqueous solution of alcohol to obtain L-carnitine orotate; wherein the molar ratio of the orotic acid to the ammonia is 1: 1-2; the mass percentage of the alcohol in the alcohol water solution is 5-15%; the molar ratio of the orotic acid ammonium salt to the L-carnitine is 1: 0.8 to 3. The method effectively improves the yield and the purity of the L-carnitine orotate, ensures the product quality, and has the advantages of simple operation, low equipment requirement and high safety factor.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of L-carnitine orotate.
Background
The L-carnitine orotate is an ion composite salt formed by pharmacologically active L-carnitine and orotic acid, and is easier to absorb after entering the body than the respective original forms of L-carnitine and orotic acid. The orotic acid can make hepatocyte proliferate and liver enzyme system normalize, L-carnitine can be used as biological stimulant of fat metabolism to promote oxidation process of free fatty acid in liver, L-carnitine orotate can be used as lipophilic fatty factor to play an effective role, and can be used for adjuvant treatment of various hepatitis, liver cirrhosis, fatty liver, hepatosis, alcoholic liver function injury, etc. Therefore, the research on the synthesis method of the L-carnitine orotate has very important practical application value.
Wherein the structural formula of the L-carnitine orotate is as follows:
because the solubility of the orotic acid in water and an organic solvent is poor, when the L-carnitine and the orotic acid are directly used for salifying, a small amount of the orotic acid is mixed in the obtained L-carnitine orotate, so that the purity can not reach the standard; or a large amount of solvent is used, so that the crystallization yield is greatly reduced, and the salt is difficult to prepare by adopting the L-carnitine and the orotic acid. How to improve the yield, the purity and the product quality becomes a difficult problem in the preparation process of the L-carnitine orotate.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of L-carnitine orotate, which comprises the steps of firstly reacting orotic acid with ammonia to generate ammonium orotate, reacting the ammonium orotate with L-carnitine in an alcohol aqueous solution, and utilizing the solubility difference between a product and a raw material to further obtain the L-carnitine orotate.
In order to achieve the technical purpose, the invention adopts the specific technical scheme that the preparation method of the L-carnitine orotate comprises the following steps: step a, reacting orotic acid with ammonia to generate orotic acid ammonium salt; step b, reacting orotate ammonium salt with L-carnitine in an aqueous solution of alcohol to obtain L-carnitine orotate; wherein the molar ratio of the orotic acid to the ammonia is 1: 1-2; the mass percentage of the alcohol in the alcohol water solution is 5-15%; the molar ratio of the orotic acid ammonium salt to the L-carnitine is 1: 0.8 to 3.
As an improved technical scheme of the invention, the molar ratio of the orotic acid to the ammonia is preferably 1: 1.2.
As an improved technical scheme of the invention, the alcohol in the alcohol aqueous solution can be methanol, ethanol or isopropanol.
As an improved technical scheme of the invention, the mass percentage of the alcohol in the alcohol aqueous solution is preferably 10%.
As an improved technical scheme of the invention, the molar ratio of the orotate ammonium salt to the L-carnitine is preferably 1: 1.5.
As an improved technical scheme of the invention, the step a is specifically to dissolve orotic acid in water, heating the water to 70-80 ℃, adding ammonia water with the mass concentration of 25% under the stirring condition, reacting at a constant temperature for 0.5-2 hours, concentrating after the reaction is finished, cooling and crystallizing, and filtering to obtain orotic acid ammonium salt; wherein the mass ratio of the orotic acid to the water is 39: 500.
As an improved technical scheme of the invention, the isothermal reaction time is preferably 1.5 hours.
And b, as an improved technical scheme of the invention, adding ammonium orotate into an alcohol aqueous solution, heating to 60-80 ℃ to enable the ammonium orotate to be dissolved clearly, adding L-carnitine, reacting for 1-4 hours at constant temperature, cooling to 0 ℃, separating out a product, and filtering to obtain the L-carnitine orotate.
As an improved technical scheme of the invention, the time of isothermal reaction is preferably 3 h.
The chemical reaction formula of the preparation method adopted by the invention is shown as formula I and formula II.
Reaction of orotic acid with ammonia of formula i:
formula ii, reaction of ammonium orotate with l-carnitine:
advantageous effects
Firstly, the invention utilizes the solubility difference of ammonium orotate and L-carnitine orotate in an alcohol aqueous solution to obtain a product through an ion exchange reaction, and the obtained product has higher yield (the total yield of two steps is more than 90 percent) and higher purity (more than or equal to 99 percent).
Secondly, the aqueous solution of the alcohol used in the invention is a reaction solvent and a crystallization solvent, the reaction condition and the crystallization condition can be adjusted by adjusting the proportion of the alcohol and the water, the operation is simple, and the equipment requirement is low.
In conclusion, the technical scheme of the invention effectively improves the yield and purity of the L-carnitine orotate, ensures the product quality, and has the advantages of simple operation, low equipment requirement and high safety factor.
Detailed Description
In order to make the purpose and technical solution of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention.
It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the prior art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
The preparation method of L-carnitine orotate comprises the steps of reacting orotic acid with ammonia water to obtain amine salt, dissolving the amine salt and L-carnitine into a mixed solution of alcohol and water by utilizing the good solubility of ammonium orotate, and separating out L-carnitine orotate with low solubility through ion exchange.
The preparation method specifically comprises the following steps:
(1) dissolving 156g (1 mol) of orotic acid in 2000mL of water, heating to 70-80 ℃, adding 210g (1.5 mol) of 25% concentrated ammonia water while stirring, keeping the temperature for reaction for 0.5-2 hours (preferably 1.5 hours), after the reaction is finished, concentrating, cooling for crystallization, and filtering to obtain orotic acid ammonium salt; wherein the molar ratio of the orotic acid to the ammonia is 1:1 to 2 (preferably 1: 1.2).
(2) Adding orotic acid ammonium salt into an alcohol aqueous solution (the alcohol can be methanol, ethanol and isopropanol, preferably ethanol, the mass percent of the ethanol and the water is 5-15%, preferably 10%), heating to 60-80 ℃ for dissolving, adding L-carnitine, keeping the temperature for reacting for 1-4 hours (preferably 3 hours), cooling to 0 ℃, separating out a product, and filtering to obtain L-carnitine orotate; wherein the molar ratio of the orotic acid ammonium salt to the L-carnitine is 1: 0.8 to 3 (preferably 1: 1.5).
Example 1
(1) Dissolving 156g (1 mol) of orotic acid in 2000mL of water, heating to 80 ℃, adding 1.2mol of ammonia water with the mass percentage concentration of 25% while stirring, keeping the temperature for reaction for 1.5 hours, concentrating after the reaction is finished, cooling for crystallization, and filtering to obtain orotic acid ammonium salt;
(2) adding the obtained orotic acid ammonium salt into 2700mL of ethanol aqueous solution, wherein the mass percentage of ethanol is 10%, heating to 80 ℃ to dissolve and clear lactate, adding 241.8g of L-carnitine, keeping the temperature for reaction for 3 hours, cooling to 0 ℃, separating out a product, and filtering to obtain 296g of L-carnitine orotate.
And (3) comparing the retention time of the product with that of the L-carnitine orotate standard substance through liquid phase detection to determine that the product is L-carnitine orotate. And determining the content by using a liquid phase normalization method: agilent model 1100 HPLC was used, and the liquid column used was Agilent SB C8(150 mm. times.4.6 mm, 5 μm), mobile phase: 0.02mol/L phosphoric acid solution, flow rate: 1.0 ml/min, temperature: 30 ℃, detection wavelength: 254nm, retention time of L-carnitine orotate: 4.95 minutes, the yield was 93.4%, the L-carnitine orotate content was 99.5%.
Example 2
(1) Dissolving 156g (1 mol) of orotic acid in 2000mL of water, heating to 80 ℃, adding 1mol of ammonia water with the mass percentage concentration of 25% while stirring, keeping the temperature for reaction for 0.5 hour, after the reaction is finished, concentrating, cooling for crystallization, and filtering to obtain orotic acid ammonium salt;
(2) adding the obtained orotate ammonium salt into 2700mL of methanol aqueous solution, wherein the mass percent of methanol is 5%, heating to 60 ℃ to dissolve and clear lactate, adding 128.96g of L-carnitine, keeping the temperature for reaction for 1 hour, cooling to 0 ℃, separating out the product, and filtering to obtain 289.1g of L-carnitine orotate. The yield was 91.2% and the L-carnitine orotate content was 99.4%.
Example 3
(1) Dissolving 156g (1 mol) of orotic acid in 2000mL of water, heating to 80 ℃, adding 2mol of ammonia water with the mass percentage concentration of 25% while stirring, keeping the temperature for reaction for 2 hours, after the reaction is finished, concentrating, cooling and crystallizing, and filtering to obtain 170g of orotic acid ammonium salt;
(2) 170g of orotate ammonium salt is added into 2700mL of isopropanol aqueous solution, wherein the mass percentage of isopropanol is 15%, the temperature is increased to 70 ℃ to dissolve and clear lactate, 483.6g of L-carnitine is added, the temperature is kept for reaction for 4 hours, the temperature is reduced to 0 ℃, products are separated out, and the L-carnitine orotate 292.6g is obtained after filtration. The yield was 92.3% and the L-carnitine orotate content was 99.3%.
Example 4
(1) Dissolving 156g (1 mol) of orotic acid in 2200mL of water, heating to 80 ℃, adding 210g (1.5 mol) of ammonia water with the mass concentration of 25% while stirring, keeping the temperature for reaction for 2.5 hours, concentrating after the reaction is finished, cooling for crystallization, and filtering to obtain 160g of orotic acid ammonium salt;
(2) 160g of orotate ammonium salt is added into 2600mL of 10% methanol aqueous solution, the temperature is increased to 65 ℃ for dissolving, 223g of L-carnitine is added, the temperature is kept at the temperature for reaction for 3.5 hours, the temperature is reduced to 0 ℃, products are separated out, and 287.2g of L-carnitine orotate is obtained after filtration, the yield is 90.6%, and the content of the L-carnitine orotate is 99.1%.
The above are merely embodiments of the present invention, which are described in detail and with particularity, and therefore should not be construed as limiting the scope of the invention. It should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the spirit of the present invention, and these changes and modifications are within the scope of the present invention.
Claims (4)
1. The preparation method of the L-carnitine orotate is characterized by comprising the following steps:
step a, reacting orotic acid with ammonia to obtain orotic acid ammonium salt;
step b, reacting orotate ammonium salt with L-carnitine in an aqueous solution of alcohol to obtain L-carnitine orotate; wherein the molar ratio of the orotic acid to the ammonia is 1: 1.2; the mass percentage of the alcohol in the alcohol aqueous solution is 10 percent; the molar ratio of the orotic acid ammonium salt to the L-carnitine is 1: 1.5.
2. The method of claim 1, wherein the alcohol in the aqueous solution of alcohol is methanol, ethanol or isopropanol.
3. The preparation method of L-carnitine orotate according to claim 1, wherein said step a is specifically that orotic acid is dissolved in water, the temperature is raised to 70-80 ℃, ammonia water with a mass concentration of 25% is added under stirring, the reaction is carried out at a constant temperature for 1.5 hours, after the reaction is finished, the reaction is concentrated, cooled and crystallized, and ammonium orotate is obtained by filtration; wherein the mass ratio of the orotic acid to the water is 39: 500.
4. The method for preparing L-carnitine orotate according to claim 1, wherein said step b comprises adding ammonium orotate to an alcohol aqueous solution, heating to 60-80 ℃ to make the ammonium orotate salt clear, adding L-carnitine, reacting at constant temperature for 3 hours, cooling to 0 ℃, precipitating the product, and filtering to obtain L-carnitine orotate.
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US4602039A (en) * | 1983-12-28 | 1986-07-22 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Salts of-carnitine and alkanoyl L-carnitines and process for preparing same |
CN1244191A (en) * | 1996-05-31 | 2000-02-09 | 希格马托制药工业公司 | Stable, non-hygroscopic salts of L(-) carnitine and alkanoyl L(-) carnitinges, process for their preparation and solid, orally administrable compositions containing such salts |
CN104276986A (en) * | 2013-07-12 | 2015-01-14 | 辽宁科硕营养科技有限公司 | Method for preparing taurine L-carnitine |
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JPS375199B1 (en) * | 1959-12-28 | 1962-06-19 |
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Patent Citations (3)
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US4602039A (en) * | 1983-12-28 | 1986-07-22 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Salts of-carnitine and alkanoyl L-carnitines and process for preparing same |
CN1244191A (en) * | 1996-05-31 | 2000-02-09 | 希格马托制药工业公司 | Stable, non-hygroscopic salts of L(-) carnitine and alkanoyl L(-) carnitinges, process for their preparation and solid, orally administrable compositions containing such salts |
CN104276986A (en) * | 2013-07-12 | 2015-01-14 | 辽宁科硕营养科技有限公司 | Method for preparing taurine L-carnitine |
Non-Patent Citations (2)
Title |
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"Studies on Pharmaceutical Preparations of Orotic Acid. II";Hiromi Nakatani;《YAKUGAKU ZASSHI》;19631231;第83卷(第1期);第312-313页 * |
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