CN111233686A - Method for recrystallizing levocarnitine - Google Patents
Method for recrystallizing levocarnitine Download PDFInfo
- Publication number
- CN111233686A CN111233686A CN202010172935.3A CN202010172935A CN111233686A CN 111233686 A CN111233686 A CN 111233686A CN 202010172935 A CN202010172935 A CN 202010172935A CN 111233686 A CN111233686 A CN 111233686A
- Authority
- CN
- China
- Prior art keywords
- levocarnitine
- acetone
- ethanol
- product
- mixed solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for recrystallizing levocarnitine, which comprises the steps of heating a mixed solution of ethanol and acetone, dissolving a crude levocarnitine product, adsorbing impurities insoluble in the mixed solution by using activated carbon, and recrystallizing the crude levocarnitine product by subsequent cooling, wherein the yield of the crude levocarnitine product exceeds 85%, especially the crude levocarnitine product is taken as a solvent after ethanol and acetone are mixed in equal amount, the improvement on the yield of levocarnitine is obviously promoted, the purity of the obtained levocarnitine is not lower than 99.5%, and the levocarnitine product meets the medical standard.
Description
Technical Field
The invention relates to purification of a pharmaceutical compound, in particular to a method for recrystallizing levocarnitine.
Background
L-carnitine, also known as L-carnitine, has a molecular formula of C7H15NO3 and a molecular weight of 161.20, is a rare vitamin B group physiologically active substance, and is an in-vivo natural substance necessary for energy metabolism of mammals; is a component of food, widely exists in nature, the goat meat has the highest content of about 2.1g/kg, and the vegetable food has little or no content, and is considered as a nutrient of a retinoid. Human body itself can synthesize levocarnitine, and about 20 g of levocarnitine exists in adult bodies and is mainly distributed in cardiac muscle and skeletal muscle. Levocarnitine is an essential cofactor for fatty acid metabolism.
At present, levocarnitine injections comprise injection and freeze-dried powder injection, and if the existing levocarnitine injections are placed for a long time, the colors of the existing levocarnitine injections slightly turn yellow, and the existing levocarnitine injections are determined to be caused by the fact that dextrorotation products of the existing levocarnitine injections are increased and are easy to degrade. In the prior art, the purification yield of the levocarnitine is about 60 percent generally, and the process flow is complex.
The design of a low-cost and high-efficiency method for recrystallizing levocarnitine is a technical problem which needs to be solved urgently by a person skilled in the art.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a low-cost and high-efficiency method for recrystallizing levocarnitine.
In order to solve the technical problems, the method for recrystallizing the levocarnitine provided by the invention comprises the following steps:
step a, adding a mixed solution of ethanol and acetone into a reactor as a solvent, dissolving a crude levocarnitine product in the mixed solution of the ethanol and the acetone, and heating to 55-60 ℃ to completely dissolve the crude levocarnitine product;
b, adding activated carbon into the mixed solution, stirring for 1-2 hours, adsorbing undissolved impurities in the crude levocarnitine product by using the activated carbon, filtering to remove the activated carbon, and collecting filtrate;
and c, cooling the filtrate to 0-10 ℃, stirring for not less than 2 hours, then filtering to obtain a levocarnitine filter cake, washing the levocarnitine filter cake with acetone, and drying the levocarnitine filter cake in vacuum at 43-47 ℃ for 5-8 hours until the quality of the levocarnitine filter cake is not changed any more, so as to obtain a white solid levocarnitine pure product.
Further, in the step a, the mass ratio of the solute crude levocarnitine product to the mixed solution of ethanol and acetone is 1: 6.5-12.
Further, in the step a, the mass ratio of the solute crude levocarnitine product to the mixed solution of ethanol and acetone is 1: 8.
Further, in the step a, the mass ratio of the ethanol to the acetone in the mixed solution of the ethanol and the acetone is 1: 1.
Further, in the step c, the levocarnitine filter cake is dried in vacuum at 45 ℃.
The invention has the technical effects that: compared with the prior art, the method for recrystallizing the levocarnitine dissolves a crude levocarnitine product after heating the mixed solution of ethanol and acetone, adsorbs impurities which are insoluble in the mixed solution by using activated carbon, recrystallizes the crude levocarnitine product through subsequent cooling, has the yield of over 85 percent, particularly has obvious promotion on the improvement of the yield of the levocarnitine after the ethanol and the acetone are mixed in equal amount and is used as a solvent, and the purity of the obtained levocarnitine is not lower than 99.5 percent and meets the medical standard.
Detailed Description
To further illustrate the present invention, some specific embodiments are described below, and some implementation methods of the present invention are described in conjunction with specific operation procedures.
Example 1
A method for recrystallizing levocarnitine comprises the following process routes:
firstly, the research of solvent type selection is carried out, and the selected sample is a crude levocarnitine product which is oily (needle-shaped solid is separated out after standing overnight).
Common mixed solution of ethyl acetate, dichloromethane, acetone, methanol, ethanol, isopropanol, ethanol and acetone is selected as the solvent, and tests are carried out at different temperatures, and specific results are shown in table 1.
TABLE 1 investigation of solvent species
Wherein the serial number 8 adopts a mixed solution of ethanol and acetone, the weight ratio of the ethanol in the mixed solution is 25 percent, the weight ratio of the acetone in the mixed solution is 75 percent, and the mass ratio of the crude levocarnitine product to the mixed solution of the ethanol and the acetone is 1: 4; the serial number 9 adopts a mixed solution of ethanol and acetone, wherein the weight ratio of the ethanol in the mixed solution is 40 percent, the weight ratio of the acetone in the mixed solution is 60 percent, and the mass ratio of the crude levocarnitine product to the mixed solution of the ethanol and the acetone is 1: 4; the serial number 10 adopts a mixed solution of ethanol and acetone, the weight ratio of the ethanol in the mixed solution is 50%, the weight ratio of the acetone in the mixed solution is 50%, and the mass ratio of the crude levocarnitine product to the mixed solution of the ethanol and the acetone is 1: 8.
The following conclusions can be drawn from the 10 tests of table 1:
1) the impurities in the crude levocarnitine product can be dissolved in water, methanol and ethanol, but the solubility in ethyl acetate, dichloromethane and acetone is poor, so that the crude levocarnitine product cannot be refined by a method of firstly removing a large amount of impurities by using a fat-soluble solvent, and improving the purity of the levocarnitine in the crude levocarnitine product;
2) the solvent type of the refining process is selected from a mixed solution system of ethanol and acetone, and the mass ratio of the ethanol to the acetone is 1: 1.
On the basis, the solvent dosage is researched, and the selected sample is still a crude levocarnitine product and is oily (needle-shaped solid is separated out after standing overnight). The ratios of ethanol and acetone in the solution were differentiated and a number of tests were performed, the specific results are shown in table 2.
TABLE 2 investigation of solvent dosage
The following conclusions can be drawn from the 4 tests of table 2: the best refining process at present is to use 8 times of the weight of the ethanol and acetone mixed solution of the crude levocarnitine product for recrystallization.
On the basis, the mixed solution of ethanol and acetone is used for carrying out the recrystallization on the crude levocarnitine product for mass production, and concretely, the method comprises the following steps,
step a, adding 800g of mixed solution of ethanol and acetone into a reactor as a solvent, wherein the weight ratio of ethanol to acetone in the mixed solution of ethanol and acetone is 50%, and the weight ratio of acetone is 50%; dissolving 100.0g of crude levocarnitine product in a mixed solution of ethanol and acetone, and heating to 55-60 ℃ to completely dissolve the crude levocarnitine product;
step b, adding 5g of activated carbon into the mixed solution, stirring for 1.5 hours, adsorbing undissolved impurities in the crude levocarnitine product by using the activated carbon, then filtering to remove the activated carbon, and collecting filtrate;
and c, slowly cooling the filtrate to 0-10 ℃, stirring for 2 hours, then filtering to obtain a levocarnitine filter cake, washing the levocarnitine filter cake with acetone, and drying the levocarnitine filter cake in vacuum at 45 ℃ for 6 hours until the mass of the levocarnitine filter cake is not changed any more, so as to obtain a white solid levocarnitine pure product, wherein the yield is 85.2g and the purity is 99.52 percent by weighing the white solid levocarnitine pure product.
Example 2
On the basis of example 1, the method for recrystallizing levocarnitine in this example has the following changes:
step a, adding 1200g of mixed solution of ethanol and acetone into a reactor as a solvent, wherein the weight ratio of ethanol to acetone in the mixed solution of ethanol and acetone is 50%, and the weight ratio of acetone is 50%; dissolving 150.0g of crude levocarnitine product in a mixed solution of ethanol and acetone, and heating to 55-60 ℃ to completely dissolve the crude levocarnitine product;
step b, adding 8g of activated carbon into the mixed solution, stirring for 2 hours, adsorbing undissolved impurities in the crude levocarnitine product by using the activated carbon, filtering to remove the activated carbon, and collecting filtrate;
and c, slowly cooling the filtrate to 0-10 ℃, stirring for 2.5 hours, then filtering to obtain a levocarnitine filter cake, washing the levocarnitine filter cake by using acetone, and drying the levocarnitine filter cake in vacuum at 45 ℃ for 5 hours until the mass of the levocarnitine filter cake is not changed any more, so that a white solid levocarnitine pure product is obtained, wherein the white solid levocarnitine pure product is weighed to be 127.9g, so that the yield is 85.3%, and the purity is 99.54%.
Example 3
On the basis of example 1, the method for recrystallizing levocarnitine in this example has the following changes:
step a, adding 400g of mixed solution of ethanol and acetone into a reactor as a solvent, wherein the weight ratio of ethanol to acetone in the mixed solution of ethanol and acetone is 50%, and the weight ratio of acetone is 50%; dissolving 50.0g of crude levocarnitine product in a mixed solution of ethanol and acetone, and heating to 55-60 ℃ to completely dissolve the crude levocarnitine product;
step b, adding 5g of activated carbon into the mixed solution, stirring for 1 hour, adsorbing undissolved impurities in the crude levocarnitine product by using the activated carbon, filtering to remove the activated carbon, and collecting filtrate;
and c, slowly cooling the filtrate to 0-10 ℃, stirring for 2 hours, then filtering to obtain a levocarnitine filter cake, washing the levocarnitine filter cake with acetone, and drying the levocarnitine filter cake in vacuum at 45 ℃ for 4 hours until the mass of the levocarnitine filter cake is not changed any more, so as to obtain a white solid levocarnitine pure product, wherein the white solid levocarnitine pure product is weighed to be 42.8g, so that the yield is 85.6%, and the purity is 99.53%.
Comparative example 1
In the prior art, an ethanol solution is used as a solvent, and the final yield is only about 50%; the method specifically comprises the following steps:
step a, adding 40g of ethanol solution as a solvent into a reactor, dissolving 10.0g of crude levocarnitine product in the ethanol solution, and heating to 10-15 ℃ to completely dissolve the crude levocarnitine product;
step b, adding 3g of activated carbon into the mixed solution, stirring for 2 hours, adsorbing undissolved impurities in the crude levocarnitine product by using the activated carbon, filtering to remove the activated carbon, and collecting filtrate;
and c, slowly cooling the filtrate to 0-4 ℃, stirring for 2 hours, then filtering to obtain a levocarnitine filter cake, washing the levocarnitine filter cake by using acetone, and drying the levocarnitine filter cake in vacuum at 45 ℃ for 5 hours until the mass of the levocarnitine filter cake is not changed any more, so as to obtain a white solid levocarnitine pure product, wherein the white solid levocarnitine pure product is weighed to be 5.05g, so that the yield is 50.5%, and the purity is 99.0%.
It should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And such obvious variations or modifications which fall within the spirit of the invention are intended to be covered by the scope of the present invention.
Claims (5)
1. A method for recrystallizing levocarnitine is characterized by comprising the following steps:
step a, adding a mixed solution of ethanol and acetone into a reactor as a solvent, dissolving a crude levocarnitine product in the mixed solution of the ethanol and the acetone, and heating to 55-60 ℃ to completely dissolve the crude levocarnitine product;
b, adding activated carbon into the mixed solution, stirring for 1-2 hours, adsorbing undissolved impurities in the crude levocarnitine product by using the activated carbon, filtering to remove the activated carbon, and collecting filtrate;
and c, cooling the filtrate to 0-10 ℃, stirring for not less than 2 hours, then filtering to obtain a levocarnitine filter cake, washing the levocarnitine filter cake with acetone, and drying the levocarnitine filter cake in vacuum at 43-47 ℃ for 5-8 hours until the quality of the levocarnitine filter cake is not changed any more, so as to obtain a white solid levocarnitine pure product.
2. The method for recrystallizing levocarnitine according to claim 1, wherein in the step a, the mass ratio of the solute levocarnitine crude product to the ethanol-acetone mixed solution is 1: 6.5-12.
3. The method for recrystallizing levocarnitine according to claim 2, wherein in the step a, the mass ratio of the solute levocarnitine crude product to the ethanol-acetone mixed solution is 1: 8.
4. The method for recrystallizing levocarnitine according to claim 3, wherein in the step a, the mass ratio of ethanol to acetone in the mixed solution of ethanol and acetone is 1: 1.
5. A method for recrystallizing levocarnitine according to claim 4 wherein in said step c, the cake of levocarnitine is dried under vacuum at 45 ℃.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019113493090 | 2019-12-24 | ||
| CN201911349309 | 2019-12-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111233686A true CN111233686A (en) | 2020-06-05 |
Family
ID=70871800
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010172935.3A Withdrawn CN111233686A (en) | 2019-12-24 | 2020-03-13 | Method for recrystallizing levocarnitine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111233686A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114249665A (en) * | 2021-12-07 | 2022-03-29 | 安徽普利药业有限公司 | Preparation method of levocarnitine bulk drug |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020575A (en) * | 2010-12-09 | 2011-04-20 | 浙江工业大学 | Synthesis method of L-carnitine |
| CN110483316A (en) * | 2019-09-11 | 2019-11-22 | 武汉理工大学 | The method of asymmetric synthesis of l-carnitine |
-
2020
- 2020-03-13 CN CN202010172935.3A patent/CN111233686A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020575A (en) * | 2010-12-09 | 2011-04-20 | 浙江工业大学 | Synthesis method of L-carnitine |
| CN110483316A (en) * | 2019-09-11 | 2019-11-22 | 武汉理工大学 | The method of asymmetric synthesis of l-carnitine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114249665A (en) * | 2021-12-07 | 2022-03-29 | 安徽普利药业有限公司 | Preparation method of levocarnitine bulk drug |
| CN114249665B (en) * | 2021-12-07 | 2024-01-23 | 安徽普利药业有限公司 | Preparation method of levocarnitine bulk drug |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105503580B (en) | A kind of extraction separation method of nervonic acid | |
| US11384109B2 (en) | Method for separating phenolic acid glucoside compounds from Diaphragma juglandis Fructu | |
| CN113185485B (en) | Semi-synthesis method of dihydroquercetin | |
| CN104557967B (en) | A kind of production method of high-purity mibemycin | |
| CN112028865A (en) | Method for extracting and preparing high-content dihydromyricetin from vine tea | |
| CN111233686A (en) | Method for recrystallizing levocarnitine | |
| US11180445B2 (en) | Method for recycling urea in urea adduct process | |
| CN101143887A (en) | Method for separating and preparing corosolicacid in loquat leaf | |
| CN116970018B (en) | Ergosterol preparation and extraction method | |
| CN103145668A (en) | New technology for preparing luteolin by using hesperidin | |
| CN104447789A (en) | Preparation method of high-purity refined salinomycin sodium salt | |
| CN101985440B (en) | Method for producing piperine | |
| CN103980481B (en) | The preparation method of watermiscible vitamin E | |
| CN110627807A (en) | Bilobalide B raw material and preparation method thereof | |
| CN112321658B (en) | Method for extracting anthocyanin in aronia melanocarpa fruit | |
| TWI653331B (en) | Method for extracting sesame lignan from by-products produced by producing sesame oil | |
| CN106632207B (en) | A kind of preparation method of high-purity GCG | |
| CN108299538B (en) | Method for removing isoursodesoxycholic acid in duck bile | |
| CN114933529B (en) | Method for separating and preparing high-purity ethyl nervonate from acer truncatum kernel | |
| CN102603852A (en) | Preparation method of tripterine | |
| JP4393640B2 (en) | Production of plant sterols | |
| CN106755254B (en) | Method for synthesizing lipoic acid sterol ester in organic phase through enzyme catalysis | |
| CN104496815A (en) | Preparation method of medicinal chlorogenic acid | |
| CN103159818B (en) | Hyodeoxycholic acid refining method | |
| CN112047989B (en) | Paedenin methyl ester monomer compound, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20200605 |