Method for preparing crystalline L-carnitine

Abstract

The invention discloses a method for preparing crystalline L-carnitine, which comprises the step of crystallizing L-carnitine in a mixed solvent consisting of cyclohexane and alcohol, and the alcohol is selected from one or more of n-propanol, isobutanol and n-butanol.

Description

TECHNICAL FIELD

[0001] The present invention relates to a method for preparing crystalline L-carnitine. In particular, the present invention relates to a method for isolating and crystallizing L-carnitine from an aqueous solution. BACKGROUND

[0002] L-carnitine is a naturally occurring quaternary ammonium acid involved in the metabolic processes of most mammals, plants, and some bacteria. L-carnitine, also known as vitamin Bt, has a molecular structure as shown in Formula (I). L-carnitine plays a key role in energy production by transporting long-chain fatty acids to the mitochondria, where they are oxidized and energy is produced. L-carnitine also plays an important role in regulating metabolic pathways involved in skeletal muscle protein balance. In addition, L-carnitine is an antioxidant and anti-inflammatory compound. Therefore, L-carnitine is widely used in the field of nutritional supplements and feed additives.

[0003] Although there are various methods for synthesizing L-carnitine, only two processes are currently used for commercial production.

[0004] The first process is the fermentation oxidation of gamma-butyrobetaine, which has the following reaction formula: .

[0005] The second process uses epichlorohydrin as a starting material and is currently the main production process for L-carnitine. The reaction steps are as follows: .

[0006] Racemic epichlorohydrin can be efficiently resolved using a Salen cobalt catalyst to obtain (S)-epichlorohydrin with high yield and optical purity. Subsequently, (S)-epichlorohydrin reacts with trimethylamine hydrochloride to form L-3-chloro-2-hydroxypropyltrimethylammonium chloride (II), which then reacts with sodium cyanide to form L-carnitine nitrile chloride (III). The above two reactions can be carried out in aqueous phase by one-pot method without the need to separate the intermediate (II). After the separation and purification of L-carnitine nitrile chloride, hydrolysis in concentrated hydrochloric acid can obtain L-carnitine and ammonium chloride. Finally, L-carnitine is separated from the solution containing L-carnitine, excess hydrochloric acid, and ammonium chloride. The process based on the above reaction route has been described in U.S. Patent No. 9,096,493.

[0007] In the industrial production of L-carnitine, its aqueous solution can usually be obtained after desalination and further purification. Since L-carnitine has strong hygroscopicity and is highly soluble in water, it needs to be crystallized by spray drying or using almost water-free organic solvents to separate L-carnitine from the aqueous solution.

[0008] When L-carnitine is isolated from an aqueous solution by spray drying, the product is obtained as a fine powder and has the characteristic odor of trimethylamine. In addition, the product can have a slight coloration due to the fact that spray drying is usually carried out at temperatures higher than 120°C. Therefore, L-carnitine obtained by spray drying is not suitable for pharmaceutical applications. In order to obtain a product with high purity, L-carnitine obtained by spray drying can be further purified by recrystallization from an organic solvent.

[0009] EP 2325164, US Patent No. 8,604,237 and WO 2011060903 disclose a method for purifying L-carnitine using a mixed solvent. The method first dissolves L-carnitine in a first solvent, which should be a solvent in which L-carnitine is highly soluble, such as methanol or ethanol. The resulting L-carnitine solution should be substantially free of water, preferably having a water content of less than 2%, more preferably less than 1%, and most preferably 0.5% (w / w). After adding pure L-carnitine seeds to the solution, a second solvent is added, which should be a solvent in which L-carnitine is insoluble or poorly soluble, such as acetone, isopropanol, isobutanol, 2-butanone, pentanol, methyl acetate, ethyl acetate, butyl acetate, tetrahydrofuran, toluene or a mixture thereof. The preferred second solvent is acetone. However, this two-solvent process cannot be used to isolate L-carnitine from an aqueous solution.

[0010] WO 2006028068 discloses a method for purifying L-carnitine by first dissolving L-carnitine in a mixed solvent of a lower alcohol and water, and then concentrating under reduced pressure to recrystallize L-carnitine, thereby improving the particle size of the crystals and reducing their hygroscopicity; or adding another solvent to the solution, which is not the lower alcohol (such as ethyl acetate) to achieve recrystallization. The water content in the mixed solvent can be used to control the particle size of the L-carnitine crystals produced.

[0011] EP 0169164 discloses a method for isolating L-carnitine from an aqueous solution of L-carnitine by concentrating the aqueous solution to dryness under vacuum, and then recrystallizing the resulting residue in a mixed solvent of ethanol-acetone (2:3 by volume) to obtain pure L-carnitine crystal product.

[0012] US Patent No. 6,342,034 discloses a process for obtaining L-carnitine crystal product from an aqueous solution by pressurized water removal. The distillation residue is then dissolved in isopropanol at 70°C and filtered to remove insoluble material. The resulting filtrate is again concentrated under reduced pressure and recrystallized in a mixed solvent of isopropanol-acetone to obtain L-carnitine in a pure form.

[0013] Generally, the above-mentioned methods for obtaining L-carnitine require complete evaporation of water from the L-carnitine aqueous solution, followed by dissolving the obtained dry solid in an alcoholic solvent such as methanol or ethanol, and then precipitating the dissolved L-carnitine by adding a second solvent such as acetone or ethyl acetate. Such methods are not only complicated to operate, but also the mixed solvents used are difficult to be effectively recovered and reused.

[0014] US Patent No. 4,708,936 relates to a method for purifying L-carnitine using isobutanol. Specifically, an aqueous solution of L-carnitine is concentrated and azeotropically dried under reduced pressure using isobutanol; then the obtained product is dissolved in isobutanol, partially recrystallized, and finally precipitated by adding acetone.

[0015] Japanese Patent JP2009102258A discloses a method for purifying L-carnitine from a mixture containing L-carnitine and its related components by recrystallizing the mixture using a solvent containing butanol.

[0016] Japanese Patent JP2009102263A relates to a method for separating and purifying L-carnitine from an aqueous solution of L-carnitine. The method involves replacing the water in the aqueous solution of L-carnitine with butanol, and then crystallizing and recrystallizing the L-carnitine in the same n-butanol. When butanol is mixed with the aqueous solution of L-carnitine, the water can be removed by azeotropic distillation to less than 1%, thereby facilitating the crystallization of L-carnitine. The mother liquor obtained after separating the L-carnitine can be recovered and used to mix with another batch of aqueous solution of L-carnitine, so as to improve the process efficiency and recovery rate of L-carnitine. However, if the operation temperature for replacing the water with n-butanol is higher than 80°C, the yield of L-carnitine will be reduced. Therefore, the operation temperature of the whole process must be controlled below 80°C. As a result, the distillation of water and butanol needs to be carried out under reduced pressure; but the azeotropic distillation under reduced pressure is not only complicated to operate, but also the solvent loss is serious.

[0017] The present invention aims to overcome the above-mentioned drawbacks, and to provide an improved method for preparing L-carnitine from an aqueous solution. Another object of the present invention is to provide a method for purifying L-carnitine. SUMMARY

[0018] The present invention discloses a method for preparing L-carnitine from an aqueous solution. The present invention also relates to a method for purifying L-carnitine. The present invention achieves the crystallization of L-carnitine by crystallizing L-carnitine in a mixed solvent composed of cyclohexane and an alcohol selected from n-propanol, isobutanol, n-butanol and mixtures thereof. The water in the solution can be effectively and economically removed by azeotropic distillation, thereby achieving the crystallization of L-carnitine. DETAILED DESCRIPTION

[0019] This invention relates to a method for preparing L-carnitine. Specifically, this invention relates to a method for preparing crystalline L-carnitine from an aqueous solution of L-carnitine by crystallization and recrystallization in a specific solvent, wherein the dehydration step is carried out under normal pressure and below the decomposition temperature of L-carnitine.

[0020] Numerous studies have shown that crystalline L-carnitine can be separated from its aqueous solution in a mixed solvent consisting of cyclohexane and an alcohol selected from n-propanol, isobutanol, butanol, and mixtures thereof. Surprisingly and unexpectedly, n-propanol, isobutanol, butanol, and mixtures thereof are suitable for removing water from L-carnitine aqueous solutions via azeotropic reaction, while ethanol and isopropanol are not.

[0021] Preferably, the alcohol is n-propanol. When n-propanol is used, its azeotropic distillation temperature does not exceed 80°C, and it can effectively remove water from the solution. In addition, n-propanol has another advantage: its odor characteristics are similar to ethanol, making it more pleasant.

[0022] The preparation method according to the present invention includes the following steps: (1) preparing an aqueous solution of L-carnitine; (2) mixing the aqueous solution with an alcohol and cyclohexane; (3) subjecting the resulting mixed solution to azeotropic distillation to remove water; (4) cooling the solution or crystal suspension to allow L-carnitine to crystallize; and (5) separating the crystallized L-carnitine by solid-liquid separation to obtain a mother liquor.

[0023] There are no particular limitations on the L-carnitine used in the preparation and purification of this invention. Suitable aqueous solutions of L-carnitine can be obtained by any known method, such as: hydrolysate of L-carnitine nitrile chloride, solution obtained by optical resolution of carnitine, solution obtained by optical resolution of carnitine nitrile chloride or carnitine amide chloride, L-carnitine solution obtained by asymmetric hydrogenation of suitable precursors, L-carnitine solution obtained by fermentation, and L-carnitine solution obtained by treatment with ion exchange resin or electrodialysis.

[0024] There is no particular limitation on the concentration of the L-carnitine aqueous solution. Its concentration can be adjusted by concentrating the aqueous solution. Preferably, the concentration of L-carnitine is 30% to 90% (by weight); more preferably, it is 50% to 90%.

[0025] In this invention, an aqueous solution of L-carnitine is mixed with an alcohol selected from n-propanol, isobutanol, butanol, and mixtures thereof, followed by the addition of cyclohexane. Alternatively, a mixed solution of the alcohol and cyclohexane can be added to the aqueous solution of L-carnitine.

[0026] There is no particular limitation on the amount of alcohol relative to L-carnitine. The concentration of L-carnitine in the alcohol solution can be 10% to 90% (by weight). Preferably, the concentration is 20% to 80%, more preferably 30% to 60%, and most preferably 30% to 50%.

[0027] There is no particular limitation on the amount of cyclohexane relative to the alcohol. Preferably, the amount of cyclohexane is 5% to 60% (by weight) of the alcohol.

[0028] To achieve L-carnitine crystallization, the water content in the solution needs to be reduced to below 5% (by weight), preferably below 3%, more preferably below 2%, and most preferably below 1%. In the method of the present invention, this can be achieved by azeotropic distillation under normal pressure. Surprisingly and unexpectedly, the presence of L-carnitine in the solution makes the azeotropic distillation process more efficient and smooth. Studies have found that when n-propanol is used as the alcohol solvent, the boiling point of the solution does not exceed 80°C, and the distillate easily separates into two phases: the upper phase contains no more than 2% water, and the lower phase is mainly water. During the azeotropic distillation process, the upper phase can be continuously refluxed into the L-carnitine solution until the water content drops to the desired level, preferably below 2%, more preferably below 1%.

[0029] During azeotropic distillation, crystalline L-carnitine may be formed. After azeotropic distillation, the resulting crystal suspension is cooled to allow L-carnitine to crystallize. Alternatively, the hot solution can be directly cooled to crystallize L-carnitine.

[0030] Crystalline L-carnitine can be separated using solid-liquid separation techniques, such as filtration, centrifugation, or pressure filtration. The resulting solid L-carnitine can be further recrystallized or dried to obtain the final product.

[0031] After separating crystalline L-carnitine, a mother liquor is obtained. Additional cyclohexane can be added to this mother liquor to further precipitate L-carnitine; alternatively, the mother liquor can be concentrated and cooled to crystallize more L-carnitine. Preferably, the mother liquor is mixed with another batch of L-carnitine aqueous solution, and then the mixed solution is subjected to azeotropic distillation to remove water, thereby achieving L-carnitine crystallization. The recycling method of the present invention can recover L-carnitine from aqueous solution in high yield, preferably greater than 90%, more preferably greater than 95%, and most preferably close to 100% quantitative recovery.

[0032] It should be noted that the method provided by the present invention has a significant advantage: the mother liquor can be recycled without separating the individual components in the mixed solvent.

[0033] The method provided by this invention can also be used to purify L-carnitine containing solid impurities to obtain a pure crystalline product. For example, when solid L-carnitine is obtained by spray drying an aqueous solution of L-carnitine, the product exhibits a slight discoloration and an amine odor. This form of L-carnitine can be effectively purified by recrystallization in a mixed solvent consisting of cyclohexane and an alcohol selected from n-propanol, isobutanol, butanol, and mixtures thereof.

[0034] The method of this invention for recrystallizing L-carnitine in a mixed solvent has significant advantages. First, the water content of the L-carnitine solution in the mixed solvent can be easily controlled by azeotropic distillation. Second, the mother liquor after separating the crystallized L-carnitine can be recycled without separating the components, thus significantly simplifying the process. Third, L-carnitine containing impurities can be easily purified into high-purity L-carnitine using this process.

[0035] After L-carnitine is isolated, it can react with L-tartaric acid to form L-carnitine L-tartrate, with fumaric acid to form L-carnitine fumarate, with acetyl chloride to form acetyl L-carnitine hydrochloride, and with propionyl chloride to form propionyl L-carnitine hydrochloride.

[0036] The process according to the present invention can be carried out in an intermittent, semi-continuous or continuous manner.

[0037] The following examples are used to illustrate the implementation of the present invention, but do not limit the scope of the present invention.

[0038] Comparative Example 1 66 g of 75% L-carnitine solution, 200 mL of ethanol, and 50 mL of cyclohexane were added to a round-bottom flask equipped with a Dean-Stark water separator. After reflux at an internal temperature of 66°C for 8 hours, the water content of the solution in the flask reached 6.0%. Under these conditions, L-carnitine failed to crystallize from the solution.

[0039] Comparative Example 2 66 g of 75% L-carnitine solution, 200 mL of isopropanol, and 50 mL of cyclohexane were added to a round-bottom flask equipped with a Dean-Stark water separator. After reflux at an internal temperature of 75°C for 8 hours, the water content of the solution in the flask reached 6.8%. Under these conditions, L-carnitine failed to crystallize from the solution.

[0040] Example 1 214 g of 75% L-carnitine solution, 860 mL of n-propanol, and 214 mL of cyclohexane were added to a round-bottom flask equipped with a Dean-Stark water separator. After azeotropic reflux at an internal temperature of 79 °C for 8 hours, the water content of the solution in the flask reached 1.0%. The solution was then slowly cooled to 20 °C to allow L-carnitine to crystallize. The resulting crystal suspension was filtered and dried to obtain 72.4 g of white crystalline L-carnitine solid, with a yield of 45.3% after drying. =31.6° (c=10, H2O), water content is 0.21%. The weight of the mother liquor is 810 g.

[0041] Example 2 The mother liquor from Example 1, 200 g of 75% L-carnitine solution, 50 mL of n-propanol, and 13 mL of cyclohexane were added to a round-bottom flask equipped with a Dean-Stark water separator. After azeotropic reflux at an internal temperature of 79°C for 8 hours, the water content of the solution in the flask reached 1.2%. The solution was then slowly cooled to 20°C to allow L-carnitine to crystallize. The resulting crystal suspension was filtered and dried to obtain 143 g of white crystalline L-carnitine solid, with a yield of 95.3% after drying. =31.3°C (c=10, H2O), water content is 0.25%. The weight of the mother liquor is 804g.

[0042] Example 3 The mother liquor from Example 2, 200 g of 75% L-carnitine solution, 50 mL of n-propanol, and 13 mL of cyclohexane were added to a round-bottom flask equipped with a Dean-Stark water separator. After azeotropic reflux at an internal temperature of 79°C for 8 hours, the water content of the solution in the flask reached 0.9%. The solution was then slowly cooled to 20°C to allow L-carnitine to crystallize. The resulting crystal suspension was filtered and dried to obtain 146.3 g of white crystalline L-carnitine solid, with a yield of 97.5% after drying. = -30.8° (c=10, H2O), water content is 0.27%. The weight of the mother liquor is 801g.

[0043] Example 4 66 g of 75% L-carnitine solution, 200 mL of isobutanol, and 50 mL of cyclohexane were added to a round-bottom flask equipped with a Dean-Stark water separator. After reflux at an internal temperature of 90 °C for 8 hours, the water content of the solution in the flask reached 1.3%. The solution was then slowly cooled to 20 °C to allow L-carnitine to crystallize. The resulting crystal suspension was filtered and dried to obtain 42.5 g of white crystalline L-carnitine solid. = -30.5° (c=10, H2O), water content is 0.23%.

[0044] Example 5 66 g of 75% L-carnitine solution, 200 mL of n-butanol, and 50 mL of cyclohexane were added to a round-bottom flask equipped with a Dean-Stark water separator. After reflux at an internal temperature of 95°C for 8 hours, the water content in the flask reached 1.2%. The solution was then slowly cooled to 20°C to allow L-carnitine to crystallize. The resulting crystal suspension was filtered and dried to obtain 40.7 g of white crystalline L-carnitine solid. = -30.9° (c=10, H2O), water content is 0.18%.

[0045] Those skilled in the art will understand that the above embodiments and descriptions are only for illustrating the present invention. Various modifications to the present invention are obvious to those skilled in the art, and such modifications should be considered to fall within the spirit and scope of this application and the protection scope of the appended claims.

Claims

1. A method for preparing crystalline L-carnitine, characterized in that, The step includes crystallizing L-carnitine in a mixed solvent consisting of cyclohexane and an alcohol selected from one or more of n-propanol, isobutanol, and butanol.

2. The method according to claim 1, characterized in that, The method includes mixing an aqueous solution of L-carnitine with the mixed solvent and removing water by azeotropic distillation.

3. The method according to claim 1, characterized in that, The alcohol is selected from n-propanol.

4. The method according to claim 1, characterized in that, The alcohol is selected from isobutanol.

5. The method according to claim 1, characterized in that, The alcohol is selected from n-butanol.

6. The method according to claim 1, characterized in that, The water content of the L-carnitine solution in the mixed solvent is less than 5% (by weight).

7. The method according to claim 1, characterized in that, The water content of the L-carnitine solution in the mixed solvent is less than 3% (by weight).

8. The method according to claim 1, characterized in that, The water content of the L-carnitine solution in the mixed solvent is less than 1% (by weight).

9. The method according to claim 1, characterized in that, The resulting L-carnitine contains cyclohexane as a residual solvent.

10. The method according to claim 1, characterized in that, The resulting L-carnitine contains no ethanol, acetone, or isopropanol.

11. The method according to claim 3, characterized in that, The resulting L-carnitine contains n-propanol as a residual solvent.

12. The method according to claim 4, characterized in that, The resulting L-carnitine contains isobutanol as a residual solvent.

13. The method according to claim 5, characterized in that, The resulting L-carnitine contains n-butanol as a residual solvent.

14. The method according to claim 1, characterized in that, It also includes the step of reacting L-carnitine with L-tartaric acid to produce L-carnitine L-tartrate.

15. The method according to claim 1, characterized in that, It also includes the step of reacting L-carnitine with fumaric acid to produce L-carnitine fumarate.

16. The method according to claim 1, characterized in that, It also includes the step of reacting L-carnitine with acetyl chloride to produce acetyl-L-carnitine hydrochloride.

17. The method according to claim 1, characterized in that, It also includes the step of reacting L-carnitine with propionyl chloride to generate propionyl-L-carnitine hydrochloride.