CN106045919A - Preparation method of L-carnitine orotate - Google Patents
Preparation method of L-carnitine orotate Download PDFInfo
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- CN106045919A CN106045919A CN201610528724.2A CN201610528724A CN106045919A CN 106045919 A CN106045919 A CN 106045919A CN 201610528724 A CN201610528724 A CN 201610528724A CN 106045919 A CN106045919 A CN 106045919A
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- carnitine
- orotic acid
- orotate
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- alcohol
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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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemical engineering, and particularly relates to a preparation method of L-carnitine orotate. The preparation method includes following steps: step a, enabling orotic acid to react with ammonium to generate ammonium orotate; step b, enabling ammonium orotate and L-carnitine to react in a water solution of alcohol to obtain L-carnitine orotate, wherein a molar ratio of the orotic acid to ammonium is 1:1-2, mass percent content of the alcohol in the water solution is 5-15%, and a molar ratio of ammonium orotate and L-carnitine is 1:0.8-3. By using the preparation method, yield and purity of L-carnitine orotate are improved effectively, and product quality is guaranteed. The preparation method is simple to operate, low in requirements on equipment and high in safety coefficient.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to the preparation method of a kind of L-carnitine Orotate.
Background technology
L-carnitine Orotate is L-carnitine and the ion complex salt of orotic acid formation having pharmacologically active, enters body
It is more easy to absorb than respective primitive form L-carnitine, orotic acid after Nei.Orotic acid just can make hepatocyte growth regulating liver-QI enzyme system
Normalizing, L-carnitine, as lipometabolic biological analeptic, can promote the oxidizing process of liver free fatty, left-handed meat
Alkali Orotate can play effective effect as parent's Adipocyte Factor, and can apply to various hepatitis, liver cirrhosis, fatty liver, liver
Poisoning, ethanol cause the auxiliary treatment of the diseases such as liver function damage.Thus, carry out the synthetic method to L-carnitine Orotate and grind
Study carefully, there is highly important actual application value.
Wherein the structural formula of L-carnitine Orotate is:
Owing to orotic acid dissolubility in water and organic solvent is the most very poor, when directly using L-carnitine to become salt with orotic acid,
Causing being mixed with a small amount of orotic acid in gained L-carnitine Orotate, purity can not be up to standard；Use a large amount of solvent, cause
Crystallization yield is substantially reduced, so it is the most difficult to use L-carnitine and orotic acid to be prepared as salt.How can improve productivity, again
Purity can be improved, it is ensured that product quality, become the difficulties in L-carnitine Orotate preparation process.
Summary of the invention
In order to solve above-mentioned technical problem, the present invention provides the preparation method of a kind of L-carnitine Orotate, and it passes through
Orotic acid and ammonia first react generation orotic acid ammonium salt, and orotic acid ammonium salt and L-carnitine react in the aqueous solution of alcohol, utilize
Product and the dissolubility difference of raw material, and then obtain L-carnitine Orotate, it effectively raises L-carnitine orotic acid
The productivity of salt and purity, it is ensured that product quality, it is simple to operate simultaneously, and equipment requirements is low, and safety coefficient is high.
In order to realize above-mentioned technical purpose, the concrete technical scheme that the present invention takes is, a kind of L-carnitine orotic acid
The preparation method of salt, comprise the steps: step a, first orotic acid and ammonia are reacted generation orotic acid ammonium salt；Step b, orotic acid
Ammonium salt and L-carnitine react in the aqueous solution of alcohol, obtain L-carnitine Orotate；Wherein, the rubbing of described orotic acid and ammonia
That ratio is 1:1～2；In the aqueous solution of described alcohol, the weight/mass percentage composition of alcohol is 5%-15%；Described orotic acid ammonium salt and left-handed meat
The mol ratio of alkali is 1:0.8～3.
The technical scheme improved as the present invention, described orotic acid is preferably 1:1.2 with the mol ratio of ammonia.
The technical scheme improved as the present invention, the alcohol in the aqueous solution of described alcohol can be methanol, ethanol or isopropanol.
The technical scheme improved as the present invention, in the aqueous solution of described alcohol, the weight/mass percentage composition of alcohol is preferably 10%.
The preferred 1:1.5 of mol ratio of the technical scheme improved as the present invention, orotic acid ammonium salt and L-carnitine.
The technical scheme improved as the present invention, described step a is specially orotic acid is soluble in water, is warmed up to 70～80
DEG C, adding mass concentration under conditions of stirring is the ammonia of 25%, and isothermal reaction 0.5～2 hours after completion of the reaction, concentrate,
Cooling crystallize, is filtrated to get orotic acid ammonium salt；Wherein orotic acid is 39:500 with the mass ratio of water.
As the technical scheme of present invention improvement, the isothermal reaction time is preferably 1.5 hours.
The technical scheme improved as the present invention, step b is specially in the aqueous solution that orotic acid ammonium salt joins alcohol, rises
Temperature is to 60～80 DEG C so that orotic acid ammonium salt is molten clearly, adds L-carnitine, isothermal reaction 1～after 4 hours, cools to 0 DEG C, analysis
Go out product, filter and i.e. obtain L-carnitine Orotate.
As the technical scheme of present invention improvement, the time of isothermal reaction is preferably 3h.
The chemical equation of preparation method of the present invention is as shown in formula I and formula II.
The reaction of formula I, orotic acid and ammonia:
；
The reaction of formula II, orotic acid ammonium salt and L-carnitine:
。
Beneficial effect
The first, the present invention utilizes orotic acid ammonium salt and L-carnitine Orotate difference of dissolubility in the aqueous solution of alcohol, logical
Crossing ion-exchange reactions, obtain product, the yield of products obtained therefrom is higher (two step total recoverys more than 90%), purity higher (>=
99%).
The second, the aqueous solution of alcohol used by the present invention had both been reaction dissolvent, was again recrystallisation solvent, by adjusting the ratio of alcohol and water
Example, it is possible to adjusting response situation and crystallization situation, simple to operate, equipment requirements is low.
In sum, technical scheme effectively raises productivity and the purity of L-carnitine Orotate, protects
Card product quality, it is simple to operate simultaneously, and equipment requirements is low, and safety coefficient is high.
Detailed description of the invention
Purpose and technical scheme for making the embodiment of the present invention are clearer, below in conjunction with the embodiment of the present invention, to this
The technical scheme of invention is clearly and completely described.Obviously, described embodiment is a part of embodiment of the present invention,
Rather than whole embodiments.Based on described embodiments of the invention, those of ordinary skill in the art are without creativeness
The every other embodiment obtained on the premise of work, broadly falls into the scope of protection of the invention.
Those skilled in the art of the present technique are appreciated that unless otherwise defined, and all terms used herein (include technology art
Language and scientific terminology) have with the those of ordinary skill in art of the present invention be commonly understood by identical meaning.Also should
Being understood by, those terms defined in such as general dictionary should be understood that the meaning having with the context of prior art
The meaning that justice is consistent, and unless defined as here, will not explain by idealization or the most formal implication.
The preparation method of a kind of L-carnitine Orotate, orotic acid reacts with ammonia and obtains amine salt, utilizes orotic acid ammonium
The preferable dissolubility of salt, is dissolved in itself and L-carnitine in the mixed solution of alcohol and water, is exchanged by ion, separates out dissolubility relatively
Little L-carnitine Orotate.
This preparation method specifically includes following steps:
(1) by 156g(1mol) orotic acid be dissolved in 2000mL water, after being warmed up to 70～80 DEG C, under stirring, add 210g
(1.5mol) strong aqua ammonia of 25%, keeping the said temperature response time is 0.5～2 hour (preferably 1.5 hours), reacts complete
After, concentrate, crystallize of lowering the temperature, be filtrated to get orotic acid ammonium salt；Wherein, the mol ratio of described orotic acid and ammonia is that 1:1～2(is preferred
1:1.2).
(2) orotic acid ammonium salt is joined in the aqueous solution of alcohol (alcohol can be methanol, ethanol, isopropanol, preferred alcohol；
The mass percent of second alcohol and water is 5%～15%, preferably 10%), it is warmed up to 60～80 DEG C and molten adds L-carnitine clearly, keep
In this thermotonus 1～4 hours (preferably 3 hours), cooling to 0 DEG C, product separates out, and filters and i.e. obtains L-carnitine Orotate；
Wherein, described orotic acid ammonium salt is the preferred 1:1.5 of 1:0.8～3(with the mol ratio of L-carnitine).
Embodiment 1
(1) by 156g(1mol) orotic acid be dissolved in 2000mL water, after being warmed up to 80 DEG C, the lower quality adding 1.2mol of stirring
Percentage concentration is the ammonia of 25%, and keeping the said temperature response time is 1.5 hours, after completion of the reaction, concentrates, crystallize of lowering the temperature,
It is filtrated to get orotic acid ammonium salt；
(2) being joined by the orotic acid ammonium salt obtained in the ethanol water of 2700mL, the weight/mass percentage composition of ethanol is here
10%, it is warmed up to 80 DEG C of molten clear salt of clear lactic acid, adds L-carnitine 241.8g, be maintained at this thermotonus 3 hours, cool to 0
DEG C, product separates out, and filters and i.e. obtains L-carnitine Orotate 296g.
Product, through Liquid Detection, carries out retention time comparison with L-carnitine Orotate standard substance, determines that product is left
Rotation carnitine Orotate.And use liquid phase normalization method to determine content: use Agilent 1100 type high performance liquid chromatography, liquid used
Phase post is Agilent SB C8 (150mm × 4.6mm, 5 μm), and flow phase: 0.02mol/L phosphoric acid solution, flow velocity: 1.0 ml/
Minute, temperature: 30 DEG C, detect wavelength: 254nm, the retention time of L-carnitine Orotate: 4.95 minutes, its yield is
93.4%, L-carnitine Orotate content is 99.5%.
Embodiment 2
(1) by 156g(1mol) orotic acid be dissolved in 2000mL water, after being warmed up to 80 DEG C, stirring is lower adds 1mol percent mass
Concentration is the ammonia of 25%, and keeping the said temperature response time is 0.5 hour, after completion of the reaction, concentrates, and crystallize of lowering the temperature filters
Obtain orotic acid ammonium salt；
(2) being joined by the orotic acid ammonium salt obtained in the methanol aqueous solution of 2700mL, the weight/mass percentage composition of methanol is here
5%, it is warmed up to 60 DEG C of molten clear salt of clear lactic acid, adds L-carnitine 128.96g, be maintained at this thermotonus 1 hour, cool to 0
DEG C, product separates out, and filters and i.e. obtains L-carnitine Orotate 289.1g.Its yield is 91.2%, L-carnitine Orotate content
It is 99.4%.
Embodiment 3
(1) by 156g(1mol) orotic acid be dissolved in 2000mL water, after being warmed up to 80 DEG C, stirring is lower adds 2mol percent mass
Concentration is the ammonia of 25%, and keeping the said temperature response time is 2 hours, after completion of the reaction, concentrates, and crystallize of lowering the temperature filters
To orotic acid ammonium salt 170g；
(2) orotic acid ammonium salt 170g is joined in the isopropanol water solution of 2700mL, the weight/mass percentage composition of isopropanol here
It is 15%, is warmed up to 70 DEG C of molten clear salt of clear lactic acid, adds L-carnitine 483.6g, be maintained at this thermotonus 4 hours, cooling
To 0 DEG C, product separates out, and filters and i.e. obtains L-carnitine Orotate 292.6g.Its yield is 92.3%, L-carnitine Orotate
Content is 99.3%.
Embodiment 4
(1) by 156g(1mol) orotic acid be dissolved in 2200mL water, after being warmed up to 80 DEG C, under stirring, add 210g(1.5mol)
Mass concentration is the ammonia of 25%, and keeping the said temperature response time is 2.5 hours, after completion of the reaction, concentrates, crystallize of lowering the temperature,
It is filtrated to get orotic acid ammonium salt 160g；
(2) orotic acid ammonium salt 160g is joined in the methanol aqueous solution of 10% of 2600mL, be warmed up to 65 DEG C molten clearly, add
L-carnitine 223g, is maintained at this thermotonus 3.5 hours, cools to 0 DEG C, and product separates out, and filters and i.e. obtains L-carnitine milk surum
Hydrochlorate 287.2g, its yield is 90.6%, and L-carnitine Orotate content is 99.1%.
These are only embodiments of the present invention, it describes more concrete and in detail, but can not therefore and be interpreted as right
The restriction of the scope of the claims of the present invention.It should be pointed out that, for the person of ordinary skill of the art, without departing from the present invention
On the premise of design, it is also possible to make some deformation and improvement, these belong to protection scope of the present invention.
Claims (9)
1. the preparation method of a L-carnitine Orotate, it is characterised in that comprise the steps: step a, first by orotic acid
Orotic acid ammonium salt is reacted into ammonia；Step b, orotic acid ammonium salt and L-carnitine react in the aqueous solution of alcohol, obtain left-handed meat
Alkali Orotate；Wherein, described orotic acid is 1:1～2 with the mol ratio of ammonia；In the aqueous solution of described alcohol, the percent mass of alcohol contains
Amount is 5%-15%；Described orotic acid ammonium salt is 1:0.8～3 with the mol ratio of L-carnitine.
The preparation method of a kind of L-carnitine Orotate the most according to claim 1, it is characterised in that described orotic acid
It is preferably 1:1.2 with the mol ratio of ammonia.
The preparation method of a kind of L-carnitine Orotate the most according to claim 1, it is characterised in that described alcohol
Alcohol in aqueous solution can be methanol, ethanol or isopropanol.
The preparation method of a kind of L-carnitine Orotate the most according to claim 1, it is characterised in that the water of described alcohol
In solution, the weight/mass percentage composition of alcohol is preferably 10%.
The preparation method of a kind of L-carnitine Orotate the most according to claim 1, it is characterised in that orotic acid ammonium salt
The preferred 1:1.5 with the mol ratio of L-carnitine.
The preparation method of a kind of L-carnitine Orotate the most according to claim 1, it is characterised in that described step a
Being specially orotic acid is soluble in water, be warmed up to 70～80 DEG C, adding mass concentration under conditions of stirring is the ammonia of 25%,
Isothermal reaction 0.5～2 hours, after completion of the reaction, concentrate, and crystallize of lowering the temperature is filtrated to get orotic acid ammonium salt；Wherein orotic acid and water
Mass ratio be 39:500.
The preparation method of a kind of L-carnitine Orotate the most according to claim 6, it is characterised in that during isothermal reaction
Between be preferably 1.5 hours.
The preparation method of a kind of L-carnitine Orotate the most according to claim 1, it is characterised in that step b is concrete
For orotic acid ammonium salt being joined in the aqueous solution of alcohol, it is warmed up to 60～80 DEG C so that orotic acid ammonium salt is molten clearly, adds left-handed meat
Alkali, isothermal reaction 1～after 4 hours, cool to 0 DEG C, separate out product, filter and i.e. obtain L-carnitine Orotate.
The preparation method of a kind of L-carnitine Orotate the most according to claim 8, it is characterised in that isothermal reaction
Time is preferably 3h.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022186617A1 (en) * | 2021-03-04 | 2022-09-09 | 제이투에이치바이오텍 (주) | Method for producing carnitine orotate using novel orotate intermediate |
| CN115745818A (en) * | 2022-11-22 | 2023-03-07 | 安徽泰格生物科技有限公司 | Preparation method of L-carnitine hydrochloride |
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| 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 | ||
| 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 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022186617A1 (en) * | 2021-03-04 | 2022-09-09 | 제이투에이치바이오텍 (주) | Method for producing carnitine orotate using novel orotate intermediate |
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| KR102552918B1 (en) * | 2021-03-04 | 2023-07-10 | 제이투에이치바이오텍(주) | Method for preparing carnitine ortate using novel ortate intermediate |
| CN115745818A (en) * | 2022-11-22 | 2023-03-07 | 安徽泰格生物科技有限公司 | Preparation method of L-carnitine hydrochloride |
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